癌症患者静脉血栓栓塞症预防NCCN2016v1

VTE Prophylaxis VTE预防

Prophylactic Anticoagulation Therapy 预防性抗凝治疗山东省肿瘤医院呼吸肿瘤内科张品良

Inpatient Prophylactic Therapy 住院患者预防性治疗

Hospitalized patients with cancer are at high risk for VTE. The panel recommends prophylactic anticoagulation therapy for all inpatients with a diagnosis of active cancer or clinical suspicion of cancer and without contraindication to such therapy (category 1). This recommendation is based on an assumption that ambulation in hospitalized cancer patients is inadequate to reduce VTE risk. Recommended anticoagulant options for VTE prophylaxis of cancer inpatients are listed within the Guidelines section Inpatient/Outpatient Prophylactic Anticoagulation Treatment. The LMWHs, fondaparinux, and subcutaneous UFH (5000 units 3 times/day) are category 1 options for inpatient prophylactic therapy. Anticoagulation therapy should be administered throughout the duration of hospitalization. Adult inpatients with cancer should undergo the following evaluation prior to the initiation of thromboprophylaxis: comprehensive medical history and physical examination; CBC with platelet count and differential; PT; aPTT; and liver and kidney function tests.
住院的癌症患者VTE高危。专家组推荐对于所有住院的诊断癌症活跃或临床怀疑恶性肿瘤且没有上述治疗禁忌症的患者进行预防性抗凝治疗(1类)。该建议是基于一种假设即在住院的癌症患者中走动不足以降低VTE风险。对于住院癌症病人的VTE预防推荐的抗凝方案在住院/门诊患者预防性抗凝治疗指南部分中列出。低分子量肝素、磺达肝素以及皮下注射普通肝素(5000u 3次/日)对于住院患者预防性治疗是1级选择。抗凝治疗应贯穿整个住院期间。住院的成年癌症患者在启动血栓预防之前应接受下列评估：全面的病史与体检；CBC与血小板计数和分类；PT；aPTT；和肝肾功能检测。

Studies comparing different anticoagulant regimens for the prevention of VTE in cancer patients have not clearly identified a particular regimen to have superior efficacy. In a randomized multicenter clinical trial, no difference in VTE and bleeding rates were seen for cancer patients receiving perioperative enoxaparin (40 mg) once daily versus low-dose UFH 3 times a day to prevent VTE after major elective abdominal or pelvic surgery. Furthermore, results from a meta-analysis of randomized clinical studies of general surgery patients found LMWHs to be as safe and effective as UFH in the prevention of VTE. However, results from a nonrandomized historically controlled study comparing the effectiveness of the LMWH dalteparin (5000 units once daily) to low- dose UFH (5000 units 3 times/day) as VTE prophylaxis in high-risk women undergoing surgery for gynecologic cancer indicated that the dalteparin dosing regimen may not be optimal in these patients. More recently, a meta-analysis comparing outcomes of perioperative VTE prophylaxis with LMWH versus UFH in cancer patients showed no difference in rates of mortality, suspected DVT, PE, or bleeding events.
比较不同抗凝方案预防癌症患者静脉血栓栓塞的研究尚未明确发现具有优越疗效的一个具体方案。在一项随机多中心临床试验中，对于较大的择期腹部或盆腔手术的肿瘤患者围手术期接受依诺肝素(40mg)每日1次对比低剂量普通肝素每天3次用于预防VTE没有见到VTE和出血率方面的差异。此外，一项来自普外科患者随机临床研究的荟萃分析结果发现低分子量肝素在VTE预防方面与普通肝素一样安全有效。但是，来自一项非随机历史对照研究比较低分子肝素达肝素(5000u qd)与低剂量普通肝素(5000u tid)作为接受手术的妇科恶性肿瘤女性高危VTE预防的疗效结果表明在这些患者中达肝素给药方案可能不是最佳的。最近，一项比较低分子肝素与普通肝素在癌症患者围手术期VTE预防结果的荟萃分析显示在死亡率、可疑深静脉血栓、肺栓塞或出血事件方面没有差异。

For prevention of catheter-related VTE, randomized controlled studies have not established the efficacy of prophylactic doses of LMWH or low- dose warfarin (1 mg daily). A recent randomized trial (n=944) showed that dose-adjusted warfarin of INR 1.5 to 2.0 was significantly more effective than fixed-dose warfarin of 1 mg daily in prevention of catheter-related VTE at a cost of a trend toward more bleeding. However, a separate comparison of warfarin between fixed 1 mg dose and adjusted dose of INR1.5 to 2 with placebo did not demonstrate a statistically significant reduction in VTE. These data suggest that therapeutic or near-therapeutic doses of anticoagulation will likely be necessary for successful prevention of catheter-related VTE. Until additional data are available, the panel does not recommend VTE prophylaxis for cancer patients with a CVAD.
对于导管相关VTE的预防，随机对照研究尚未证实预防剂量的低分子肝素或低剂量华法林(1mg/d)的疗效。最近一项随机试验(n=944)显示，INR1.5-2.0剂量调整的华法林在预防导管相关VTE方面比1mg qd固定剂量的华法林显著更有效，代价是更多的出血倾向。然而，一项独立的对照试验比较1mg固定剂量的华法林以及INR1.5-2调整剂量的华法林与安慰剂在VTE方面没有显示统计学意义的显著降低。这些数据提示治疗性或接近治疗量的抗凝将可能是成功预防导管相关VTE所必需的。在有其他可用资料以前，小组不推荐对有中心静脉导管的肿瘤患者VTE预防。

Outpatient Prophylactic Therapy in Ambulatory Cancer Patients 非卧床门诊肿瘤患者预防性治疗

Certain groups of cancer patients are known to remain at risk for VTE after discharge from the hospital. In a retrospective observational study based on data from a large cohort of cancer patients (n=17,874) identified in a health care claims database, VTE (DVT or PE) occurred in nearly 6% of patients during the 12-month index period.243 A significantly higher proportion of VTE events was diagnosed in the outpatient setting compared with the inpatient setting (78% vs. 22%; P < .0001). Moreover, among patients who had a VTE in the outpatient setting, 21% had been hospitalized within 30 days of the VTE event. This observational study suggests that a high proportion of VTE occurs in the cancer outpatient setting, and underscores the need to better identify patients who may benefit from outpatient thromboprophylaxis. The risk for VTE is sufficiently high in some surgical and medical oncology patients that VTE prophylaxis should be considered in the outpatient setting. Cancer patients undergoing abdominal or pelvic surgery should be considered for outpatient prophylaxis. Features that identify surgical oncology patients at higher risk for VTE include a previous episode of VTE, anesthesia times longer than 2 hours, advanced-stage disease, perioperative bed rest of 4 days or more, and patient aged 60 years or older. Extended prophylaxis out to 4 weeks post-surgery was associated with a more than 50% reduction in venographic VTE in patients undergoing major abdominal surgery. Since thromboembolic postoperative complications greatly exceeded hemorrhagic complications as a cause of death in the @RISTOS observational cohort study of cancer surgery patients, extended VTE prophylaxis of up to 4 weeks is recommended for cancer surgery patients, particularly the high-risk patients undergoing abdominal or pelvic surgery.
已知某些肿瘤患者群在出院后仍然有VTE风险。在一项回顾性观察研究中，根据在卫生保健机构索赔数据库中确定的一大组肿瘤患者(n=17，874)数据，在检索的12个月期间差不多6%的患者发生VTE(深静脉血栓或肺栓塞)。243 与住院情况下相比在门诊条件下确诊的VTE事件比例显著更高(78%对22%；P <.0001)。此外，在门诊确诊的vte患者当中，21%在30天内因vte事件住院。该观察研究提示在门诊的恶性肿瘤患者中出现vte的比例高，因此强调需要更好地识别可能受益于门诊血栓预防的患者。在某些外科与内科肿瘤患者中vte风险非常高所以应该考虑在门诊条件下vte预防。准备接受腹部或盆腔手术的肿瘤患者应该考虑门诊预防。具有更高vte风险的肿瘤外科患者的识别特征包括既往vte事件、感觉缺失时间长于2小时、晚期疾病、围手术期卧床休息≥4天以及年龄≥60岁。在接受较大腹部手术的患者中预防延长至术后4周以上与静脉造影静脉血栓栓塞降低>50%有关。在@RISTOS癌症手术患者的观察性队列研究中因为术后血栓栓塞并发症作为死亡的一个原因显著超过出血并发症，因此对于癌症手术患者、尤其是接受腹部或盆腔手术的高危患者推荐VTE预防延长至4周。

Although there is a lack of consistent evidence to support extended outpatient prophylaxis in most populations of ambulatory medical oncology patients, it is recommended for multiple myeloma patients receiving highly thrombogenic regimens. Immunomodulating agents with antiangiogenic properties, such as thalidomide or lenalidomide, have been associated with an increased incidence of VTE in patients with multiple myeloma in the absence of prophylaxis, although the reported rates of VTE vary widely across studies. It appears that a number of factors contribute to thrombosis associated with thalidomide or its derivatives, and VTE rates are especially high when thalidomide or lenalidomide is combined with high-dose dexamethasone of 480 mg per month, or doxorubicin or multi-agent chemotherapy regimens. In a retrospective case-control study of thalidomide or lenalidomide combined with dexamethasone in newly diagnosed patients with multiple myeloma (n=411), the incidence of VTE among the subgroup of patients who received the combination with high-dose dexamethasone (480 mg per 28-day cycle) was 19% with thalidomide and 11% with lenalidomide. Data regarding the use of routine thromboprophylaxis were not provided. In an open-label, randomized, non-inferiority trial comparing lenalidomide combined with high-dose dexamethasone (480 mg per 28-day cycle) versus with low-dose dexamethasone (160 mg per 28-day cycle) in previously untreated patients with multiple myeloma (n=445), the incidence of DVT was significantly higher among the patients receiving the combination with high-dose dexamethasone (26% vs. 12%; P = .0003). Mandatory thromboprophylaxis was added to the study protocol after enrollment of approximately 60% of the patients. The package inserts for thalidomide and lenalidomide include “black box” warnings regarding the VTE risks associated with the administration of these agents.
在大多数非卧床的肿瘤内科患者群中，尽管缺乏一致的证据支持门诊患者延长预防，但是其被推荐用于接受高血栓形成方案的多发性骨髓瘤患者。具有抗血管生成特性的免疫调节剂，如沙利度胺或来那度胺，在没有预防的情况下，与多发性骨髓瘤患者VTE发生率增加有关，尽管研究之间报道的VTE发生率变化很大。似乎许多因素促进与沙利度胺或其衍生物相关的血栓，而且当沙利度胺或来那度胺联合大剂量地塞米松480mg每月或阿霉素或多药化疗方案时VTE率特别高。在一项沙利度胺或来那度胺联合地塞米松治疗新近确诊的多发性骨髓瘤患者(n=411)的回顾性病例对照研究中，VTE的发生率在接受大剂量地塞米松(480mg每28天周期)联合沙利度胺的患者亚组当中是19%，与来那度胺联合是11%。没有提供有关常规应用血栓预防的数据。在一项标签开放、随机、非劣效性试验中比较来那度胺联合大剂量地塞米松(480mg每28天1周期)与联合低剂量地塞米松(160mg每28天1周期)治疗初治的多发性骨髓瘤患者(n=445)，在接受联合大剂量地塞米松的患者中深静脉血栓的发生率显著更高(26%对12%；P=.0003)。在大约注册60%的患者后研究设计强制加入血栓预防。沙利度胺和来那度胺包装说明书包括这些药物与给药相关的VTE风险有关的“黑框”警告。

For patients with multiple myeloma, the panel recommends a prophylaxis strategy based on a risk-assessment model published by the International Myeloma Working Group. In their publication, VTE prophylaxis with either LMWH (eg, enoxaparin 40 mg daily) or dose- adjusted warfarin (INR 2–3) is recommended for patients with multiple myeloma who are receiving lenalidomide- or thalidomide-based combination regimens associated with a high thrombotic risk or in patients with two or more individual or disease-related risk factors (see Guidelines section on VTE Risk Factors in Cancer Patients, VTE-A 2 of 3). Aspirin prophylaxis (81–325 mg daily) is an option for multiple myeloma patients receiving thalidomide or lenalidomide with one or fewer individual or multiple myeloma-specific risk factors.
对于多发性骨髓瘤患者，根据国际骨髓瘤工作组公布的一种风险评估模型专家组推荐一种预防策略。在其出版物中，对于正在接受具有高血栓形成风险的以来那度胺或沙利度胺为基础的联合方案或具有两个或以上个体或疾病相关危险因素的多发性骨髓瘤患者推荐用低分子肝素(如依诺肝素40mg/d)或剂量调整的华法林(INR2-3)VTE预防(见癌症患者VTE危险因素，VTE-A 3的2指南部分)。对于接受沙利度胺或来那度胺、具有一个或少数个体或多发性骨髓瘤特定危险因素的多发性骨髓瘤患者阿司匹林预防(81-325mg/d)是一种选择。

In a recent phase III, open-label, multicenter, randomized trial in patients with previously untreated multiple myeloma (n=667) receiving thalidomide-containing regimens, both aspirin (100 mg daily) and fixed- dose warfarin (1.25 mg daily; dose adjustment allowed to maintain INR<3) were similarly effective in reducing thromboembolic events compared with LMWH (enoxaparin 40 mg daily). The primary endpoint was a composite measure including symptomatic DVT, PE, arterial thrombosis, acute cardiovascular events, or sudden otherwise unexplained death during the first 6 months from randomization. The incidence of the composite endpoint was 6.4%, 8.2%, and 5% in the aspirin, warfarin, and LMWH groups, respectively. The absolute risk for the composite endpoint was not statistically different when comparing aspirin with LMWH (absolute difference +1.3%; P = .544) or when comparing warfarin with LMWH (absolute difference +3.2%; P = .183). Although not statistically significant, LMWH was associated with trends for decreased risks for grade 3 to 4 thromboembolic events and major bleeding events when compared with aspirin. However, LMWH was associated with a significantly decreased risk for grade 3 to 4 thromboembolic events when compared with warfarin (absolute difference +5% for warfarin vs LMWH; P = .024). Moreover, among the subgroup of patients aged 65 years or older receiving combination therapy with bortezomib, melphalan, prednisone, and thalidomide, LMWH significantly reduced the risk for the composite endpoint compared with warfarin (absolute difference +11.3 for warfarin vs. LMWH; P = .006). It should be noted that this study was conducted in myeloma patients with ”standard risk” for thromboembolism, who had no clinical indication for anticoagulation or antiplatelet therapy.
在最近一项Ⅲ期、标签开放、多中心、随机试验中初治的多发性骨髓瘤患者(n=667)接受含沙利度胺方案、阿司匹林(100mg/d)以及固定剂量的华法林(1.25mg/d；剂量调整达到并维持INR＜3)与低分子肝素(依诺肝素40mg/d)相比在降低血栓栓塞事件方面是同样有效的。主要终点是综合估量自随机化起最初6个月期间包括有症状的深静脉血栓、肺栓塞、动脉血栓形成、急性心血管事件或其他方面不能解释的突然死亡。阿司匹林、华法林和低分子肝素组复合终点的发生率分别是6.4%、8.2%和5%。阿司匹林与低分子肝素比较或华法林与低分子肝素比较复合终点绝对风险没有统计学差异，分别为绝对差别+1.3%；P=.544和+3.2%；P=.183。尽管没有显著的统计学意义，但是当与阿司匹林相比时低分子肝素与3-4度血栓栓塞事件和严重的出血事件风险降低趋势有关。然而，当与华法林相比时低分子肝素与3-4度血栓栓塞事件风险显著降低有关(华法林对低分子肝素绝对差别+5%；P =.024)。此外，在患者年龄≥65岁接受硼替佐米、美法仑、泼尼松和沙利度胺联合治疗的亚组当中，与华法林相比低分子肝素显著降低了复合终点的风险(华法林对低分子肝素绝对差别+11.3；P =.006)。值得注意的是，这项研究是在血栓栓塞“标危”的骨髓瘤患者中进行的，没有抗凝或抗血小板治疗的临床指征。

As part of a substudy of a phase III, open-label, randomized trial, thromboprophylaxis with aspirin (100 mg daily) was compared with LMWH (enoxaparin 40 mg daily) in patients with multiple myeloma (n=342) receiving lenalidomide-containing induction (combined with low-dose dexamethasone) and consolidation (combined with melphalan and prednisone). The primary endpoint was a composite measure including symptomatic DVT or PE, arterial thrombosis, acute cardiovascular events, or otherwise unexplained sudden death during the first 6 months after randomization. The incidence of the composite endpoint was not statistically different, with 2.3% in the aspirin arm and 1.2% in the LMWH arm. The incidence of DVT was 1.1% and 1.2%, respectively, and the incidence of PE was 1.7% and 0%, respectively. No patients in either treatment arm experienced arterial thrombosis, acute cardiovascular events, or sudden deaths. No major bleeding events occurred in either treatment arm; minor bleeding (involving the GI) was reported in 1 patient (<1%) in the LMWH arm. As in the case with the aforementioned phase III study of thromboprophylaxis in patients treated with thalidomide-containing regimens, the current study only included patients who had standard risk for VTE, who had no clear indication or contraindications for antiplatelet or anticoagulation therapy. Nevertheless, LMWH appeared to be more effective in preventing PE in this patient population. The investigators from this trial suggested that LMWH was preferred for thromboprophylaxis in patients at high risk for VTE during induction therapy with lenalidomide- containing regimens; in patients with no or only 1 risk factor for VTE, aspirin may be an alternative option. In addition, the investigators concluded that aspirin may also be a feasible thromboprophylaxis option during consolidation or maintenance therapy with lenalidomide.
作为一项III期、标签开放、随机试验亚组研究的一部分，在接受含来那度胺诱导(联合低剂量地塞米松)和巩固(联合美法仑和泼尼松)的多发性骨髓瘤患者(n=342)中用阿司匹林(100mg/d)血栓预防可与低分子肝素(依诺肝素40mg/d)相匹敌。主要终点是综合估量在随机化后最初6个月期间包括有症状的深静脉血栓、肺栓塞、动脉血栓形成、急性心血管事件或其他方面不能解释的猝死。复合终点的发生率没有统计学差异，阿司匹林组2.3%而低分子肝素组1.2%。深静脉血栓的发生率分别是1.1%和1.2%，而肺栓塞的发生率分别是1.7%和0%。在任一治疗组中均无患者出现动脉血栓形成、急性心血管事件或猝死。在任一治疗组中均无严重的出血事件发生；在低分子肝素组中报道1例患者(＜1%)较小的出血(涉及胃肠道)。如同前面提到的在接受含沙利度胺方案治疗的患者中血栓预防的III期研究病例，当前的研究仅仅包括静脉血栓栓塞标危患者，他们没有明确的抗血小板或抗凝治疗适应症或禁忌症。虽然如此，在预防此患者群肺栓塞方面低分子肝素似乎更有效。该试验的研究人员建议对于静脉血栓栓塞高危患者用含来那度胺方案诱导治疗期间的血栓预防低分子肝素是首选的；在没有或只有1个静脉血栓栓塞危险因素的患者中，阿司匹林可能是一个备选方案。另外，研究人员得出结论在用来那度胺巩固或维持治疗期间阿司匹林也可能是一个合理的血栓预防选择。

In light of the published data from the phase III randomized trials above, the NCCN Panel recommends prophylactic aspirin in multiple myeloma patients receiving thalidomide or lenalidomide (excluding high-risk combinations) who have no other risk factors for VTE.
根据上述III期随机试验已发表的数据，NCCN小组建议在接受沙利度胺或来那度胺(不包括高危联合)没有其他静脉血栓栓塞危险因素的多发性骨髓瘤患者中预防性给予阿司匹林。

With respect to other ambulatory cancer patients, the NCCN Panel suggests risks/benefits conversations regarding the option of thromboprophylaxis in individuals considered to be at high risk for VTE based on an assessment of VTE risk factors (see Guidelines section on VTE Risk Factors in Cancer Patients, VTE-A). Some cancer patients undergoing chemotherapy are at increased risk of developing VTE. A predictive model for chemotherapy-associated VTE has been developed26 and independently validated in several studies. The Khorana model considers the following parameters to determine the overall risk for VTE in patients with cancer: site of primary cancer (“very high risk” for stomach or pancreatic cancer; “high risk” for lymphoma, lung, gynecologic, bladder, or testicular cancer), increased pre- chemotherapy platelet count (≥350 × 10^9/L), decreased hemoglobin level (<10 or="" use="" of="" increased="" pre-chemotherapy="" leukocyte="" count="">11 × 10^9 /L), and high BMI (≥35 kg/m ). Using a scoring system that assigns risk points to each of the above parameters, patients with 0 points (none of the above risk parameters) are categorized as low risk, those with a total of 1 or 2 points are categorized as intermediate risk, and those with a total score of 3 or higher are considered high risk of developing VTE (see Guidelines section on VTE Risk Factors in Cancer Patients, VTE-A 3 of 3). In the original Khorana et al study, the rate of symptomatic VTE in the derivation cohort was 0.8%, 1.8%, and 7.1% for the low-, intermediate-, and high-risk categories, respectively. In the validation cohort, the rates were 0.3%, 2%, and 6.7%, respectively. Subsequent independent studies evaluated the utility of the Khorana scoring system in patients with cancer. Retrospective studies in patients with solid tumors and malignant lymphomas reported symptomatic VTE rates of 5% in low-risk, 16% in intermediate-risk, and 27% to 41% in high-risk patient categories. In a more recent prospective study in patients with cancer (n=819), the rates of symptomatic VTE based on the Khorana scores were 3.8% for low-risk, 9.6% for intermediate-risk, and 17.7% for high-risk patient groups.
至于其他不卧床的肿瘤患者，NCCN小组建议对个体血栓预防方案讨论风险/收益时根据静脉血栓栓塞危险因素评估考虑是否是静脉血栓栓塞高危(见癌症患者静脉血栓栓塞危险因素指南部分，VTE-A)。某些正在接受化疗的癌症患者产生静脉血栓栓塞的风险增加。已经开发出一个化疗相关静脉血栓栓塞的预测模型并在若干研究中独立证实。Khorana模型考虑下列参数以确定癌症患者VTE的风险：原发癌部位（胃和胰腺癌“非常高危”；淋巴瘤、肺癌、妇科、膀胱或睾丸癌“高危”），化疗前血小板计数升高（≥350×10^9/L）、血红蛋白降低（<10g>11×10^9/L）以及体重指数高（≥35kg/㎡）。使用评分系统对上述每个参数赋值风险得分，0分(没有任何上述风险参数)分类为低危，总分1或2分类为中危，而总分≥3认为是静脉血栓栓塞高危(见癌症患者VTE危险因素指南部分，VTE-A3/3)。在Khorana等的独创性研究中，由此推导的低、中和高危组中有症状的VTE发生率分别是0.8%、1.8%和7.1%。在验证组中，发生率分别是0.3%、2%和6.7%。随后的独立研究评估了Khorana评分系统在癌症患者中的实用性。在实体瘤与恶性淋巴瘤患者中的回顾性研究报道有症状的VTE发生率低危5%、中危16%和高危患者组27%-41%。在最近一项癌症患者(n=819)前瞻性研究中，根据Khorana评分有症状的VTE发生率低危3.8%、中危9.6%而高危患者17.7%。

Data from a randomized, placebo-controlled, double-blind trial of patients with advanced cancer undergoing treatment with chemotherapy (PROTECHT trial) showed a statistically significant decrease in thromboembolic events (composite endpoint of venous and arterial) in the group receiving prophylactic LMWH (ie, nadroparin) compared with the placebo arm. Further, in the randomized CONKO-004 trial, the symptomatic VTE rate of pancreatic cancer patients receiving chemotherapy was significantly reduced at 3 and 12 months with enoxaparin thromboprophylaxis (1mg/kg daily for 3 months followed by 40 mg daily for 3 months) compared with no LMWH. Most recently, in a large phase III, randomized, placebo-controlled trial (SAVE-ONCO) in patients with advanced cancer receiving chemotherapy (n=3212), thromboprophylaxis with the investigational ultra-LMWH semuloparin 20 mg daily was compared with placebo. The primary efficacy endpoint of this study was a composite endpoint comprising symptomatic DVT, nonfatal or fatal PE, and other death related to VTE. The main safety endpoint was clinically relevant bleeding events. The most common primary cancer sites were lung (37%) and colorectal (29%). Thromboprophylaxis was associated with a significant decrease in the primary endpoint compared with placebo (1.2% vs. 3.4%; hazard ratio, 0.36; 95% CI, 0.21–0.60; P < .001). The benefit of thromboprophylaxis was observed for both symptomatic DVT (0.7% vs. 2.1%; hazard ratio, 0.32) and nonfatal or fatal PE (0.6% vs. 1.5%; hazard ratio, 0.41). Clinically relevant bleeding (2.8% vs. 2%) and major bleeding events (1.2% vs. 1.1%) with semuloparin versus placebo were not different. Survival outcomes were not significantly different between study arms, with deaths occurring in 43% and 44.5% of patients in the semuloparin and placebo arms, respectively. It should be noted that semuloparin is an investigational agent and has not been approved by the FDA for any indication.
来自一项接受化疗治疗的晚期癌症患者随机、安慰剂对照、双盲试验(PROTECHT试验)的数据显示与安慰剂组相比接受预防性低分子肝素(即，纳屈肝素)组血栓栓塞事件(静脉与动脉复合终点)降低有显著的统计学意义。此外，在CONKO-004随机试验中，与非低分子肝素相比用依诺肝素(1mg/kg qd×3个月然后40mg qd×3个月)预防血栓显著降低正在接受化疗的胰腺癌患者在3个月和12个月时有症状的静脉血栓栓塞发生率。最近，在一项接受化疗的晚期癌症患者(n=3212)大型III期、随机、安慰剂对照试验(SAVE-ONCO)中，试验用超低分子肝素semuloparin20mg/d预防血栓与安慰剂相似。本研究的主要疗效终点是一个复合终点包括有症状的深静脉血栓、致命或非致命性肺栓塞以及其他与静脉血栓栓塞相关的死亡。主要安全性终点是临床相关的出血事件。最常见的原发癌部位是肺(37%)和结直肠(29%)。与安慰剂相比血栓预防显著降低主要终点(1.2%对3.4%；风险比，0.36；95% CI，0.21-0.60；P< .001)。对有症状的深静脉血栓(0.7%对2.1%；风险比，0.32)以及致命或非致命性肺栓塞(0.6%对1.5%；风险比，0.41)都观察到血栓预防收益。临床相关的出血(2.8%对2%)和严重的出血事件(1.2%对1.1%)semuloparin(超低分子量肝素)与安慰剂相比没有差异。研究组之间生存结果没有显著的差异，semuloparin(超低分子量肝素)和安慰剂组患者中发生死亡分别是43%和44.5%。应该注意semuloparin(超低分子量肝素)是一个试验用药并且尚未被FDA批准任何适应症。

Patients with cancer at high risk for VTE (based on Khorana risk assessment score 3 or higher) could be considered for outpatient VTE prophylaxis on an individual basis. For these patients, the NCCN Guidelines Panel recommends discussions with patients/caregivers regarding the potential risks and benefits of administering VTE prophylaxis in the outpatient setting. However, thromboprophylaxis in the majority of cancer outpatients receiving chemotherapy is controversial and its broader application using the Khorana risk assessment model or the Vienna risk assessment model should await the results of randomized controlled trials evaluating the efficacy of risk- adjusted thromboprophylaxis based on these models.
静脉血栓栓塞高危(根据Khorana风险评估评分≥3)的癌症患者可考虑在个体基础上门诊静脉血栓栓塞预防。对于这些患者，NCCN指南小组建议与患者/护理人员讨论有关在门诊条件下给予静脉血栓栓塞预防的潜在的风险与收益。然而，在大部分接受化疗的门诊癌症患者中血栓预防是有争议的并且使用Khorana风险评估模型或Vienna风险评估模型广泛应用应该有待基于这些模型评估风险调整的血栓预防疗效随机对照试验的结果。

Mechanical Prophylaxis
物理预防

Intermittent pneumatic compression (IPC) devices and GCS are mechanical prophylaxis options that are principally used in patients with contraindications to pharmacologic prophylaxis or in conjunction with pharmacologic agents in patients at very high risk for VTE. Mechanical prophylaxis should not be used in patients with an acute DVT or in the setting of severe atrial insufficiency (the latter pertains to GCS). In addition, consideration of risks and benefits should be weighed in the presence of large hematomas, thrombocytopenia (platelet count<20,000/mcL), skin ulceration or wounds (which may be more of a concern with GCS), mild arterial insufficiency (which pertains to GCS only), or peripheral neuropathy (which pertains to GCS only; see Guidelines section on Contraindications to Mechanical Prophylaxis, VTE-B). Whenever mechanical prophylaxis is employed, steps should be taken to ensure its proper use and continuous application.
间歇充气压力泵(IPC)装置与分级加压弹力袜(GCS)是主要用于有药理学预防禁忌症患者或在很高危静脉血栓栓塞患者中与药理学药物同时使用的物理预防选择。物理预防不应用于具有急性深静脉血栓或严重的房性功能不全的患者(后者适于分级加压弹力袜)。另外，在存在下列情况下应该权衡考虑风险与收益：巨大血肿、血小板减少症(血小板计数＜20000/mcL )、皮肤溃疡或伤口(其可能更担心GCS)、轻度动脉功能不全(其只适于GCS)或外周神经病(其只适于GCS；见关于物理预防禁忌症指南部分，VTE-B)。只要使用物理预防，均应采取措施以确保其正确使用并持续应用。

IPC devices have been less well-studied than the use of anticoagulation therapy in VTE prevention. Most of the data on the effectiveness of mechanical prophylaxis have come from surgical populations. For example, in a study comparing the VTE rate in gynecologic oncology surgery patients receiving either low-dose heparin 3 times a day (starting with the day before surgery and continuing for 7 days or longer after surgery) or IPC of the calf, no difference was seen between the 2 modalities. A retrospective evaluation of high-risk colorectal surgery patients who had received mechanical prophylaxis without anticoagulant therapy indicated that IPC devices were effective in preventing postoperative VTE. However, results from a retrospective study of 839 patients over a 2-year period who had undergone abdominal surgery for gynecologic cancers and received pneumatic compression and early ambulation for VTE prophylaxis found that the incidence of PE in cancer patients (4.1%) exceeded by 14-fold the incidence of PE in patients with benign disease (0.3%). Therefore, IPC devices should only be used alone for VTE prophylaxis in patients for whom anticoagulant prophylaxis is contraindicated.
在静脉血栓栓塞预防方面间歇充气压力泵装置研究不及抗凝治疗的使用充分。物理预防疗效方面的数据大部分来自外科人群。例如，在一项比较妇科肿瘤手术患者接受低剂量肝素每天3次(手术前一天开始并持续至术后7天或更长时间)或腓部间歇充气压力泵静脉血栓栓塞发生率的研究中，在这两种手段之间没有见到差异。一项高危结直肠手术患者接受物理预防没有抗凝治疗的回顾性评价显示间歇充气压力泵装置在预防术后静脉血栓栓塞方面是有效的。然而，来自一项839例妇科恶性肿瘤腹部手术并接受充气加压与早日下床活动预防静脉血栓栓塞的患者超过2年时间的回顾性研究结果发现在癌症患者中肺栓塞的发生率(4.1%)超过良性疾病患者肺栓塞发生率的14倍(0.3%)。因此，间歇充气压力泵装置应只仅用于有抗凝剂预防禁忌患者的静脉血栓栓塞预防。

GCS have been demonstrated to significantly reduce VTE in comparison to no prophylaxis and provide even greater protection when combined with other preventive therapies. However, many of these studies were conducted more than a decade ago and used fibrinogen uptake scans as a primary outcome measure—a now antiquated diagnostic method. In addition, very few of the patients were noted to have malignancies. Furthermore, a randomized controlled trial in patients undergoing hip surgery found that GCS did not provide significant additive protection against VTE in patients receiving fondaparinux 2.5 mg daily for 5 to 9 days, suggesting that GCS may not have significant clinical benefits in patients able to receive more potent forms of VTE prophylaxis. Similarly, recent results from the CLOTS1 trial, which randomly assigned patients within 1 week of stroke to routine care with or without GCS, found that GCS did not reduce the incidence of DVT in these patients and was associated with a 4-fold increase in the frequency of skin ulcers and necrosis. However, the patient group studied in the CLOTS1 trial differs considerably from the patient population described in these guidelines. Furthermore, the long delay in the institution of prophylaxis and the prolonged duration of GCS use (up to 30 days in over 70%) indicate that the safety and efficacy of GCS may be different in different populations studied under different conditions. Therefore, further investigation is warranted.
已证明与非预防相比分级加压弹力袜显著降低静脉血栓栓塞而且当与其他预防疗法联合使用时提供十分显著的防护。然而，这些研究多数是十多年前进行的并且使用纤维蛋白原摄取扫描——一种目前过时的诊断方法衡量主要转归。另外，这些患者几乎没有被记录有恶性肿瘤。此外，在接受髋部手术患者中的一项随机对照试验发现在接受磺达肝素2.5mg qd×5-9天的患者中分级加压弹力袜在防止静脉血栓栓塞方面没有提供显著的额外帮助，提示在能够接受更强形式的静脉血栓栓塞预防的患者中分级加压弹力袜可能没有显著的临床获益。同样，来自CLOTS1试验的最新结果，卒中1周内的患者随机分配至常规照顾±分级加压弹力袜，发现在这些患者中分级加压弹力袜没有降低深静脉血栓的发生率并且与皮肤溃疡和坏死发生率增加4倍有关。然而，在CLOTS1试验中研究的患者群与这些指南中描述的患者群相当不一致。此外，在机构中长时间延迟预防以及长期持续使用分级加压弹力袜(超过70%达到30天)造成分级加压弹力袜的安全性和有效性在不同人群、各种情况下的研究中可能各异。因此，已经批准进一步研究。

Until data become available, GCS should not be relied on as the sole method of VTE prophylaxis in cancer patients. Furthermore, cancer patients prescribed GCS for VTE prophylaxis should be carefully monitored for skin complications.
在获得数据前，在癌症患者中分级加压弹力袜不应被依赖作为静脉血栓栓塞预防的唯一方法。此外，嘱咐癌症患者分级加压弹力袜用于静脉血栓栓塞预防应该仔细监视皮肤并发症。