Safety and Efficacy of Apixaban vs Enoxaparin for Preventing Postoperative Venous Thromboembolism in Women Undergoing Surgery for Gynecologic Malignant Neoplasm
A Randomized Clinical Trial
阿哌沙班对比依诺肝素预防妇科恶性肿瘤术后静脉血栓栓塞的安全性与有效性：一项随机临床试验

Saketh R. Guntupalli, MD; Alyse Brennecke, MS; Kian Behbakht, MD; Anna Tayebnejad, BS; Christopher A. Breed, MD; Lisa Marie Babayan, PAC; Georgina Cheng, MD, PhD; Amin A. Ramzan, MD; Lindsay J. Wheeler, MD; Bradley R. Corr, MD; Carolyn Lefkowits, MD; Jeanelle Sheeder, PhD; Koji Matsuo, MD, PhD; Dina Flink, PhD
萨凯斯·R·贡塔帕利医学博士；艾莉丝·布伦内克理学硕士；基安·贝巴克特医学博士；安娜·塔耶布内贾德理学学士；克里斯托弗·A·布里德医学博士；丽莎·玛丽·巴巴扬医师助理；郑乔治娜医学博士/哲学博士；阿明·A·拉姆赞医学博士；林赛·J·惠勒医学博士；布拉德利·R·科尔医学博士；卡罗琳·莱夫科维茨医学博士；珍妮尔·希德哲学博士；松尾浩二医学博士/哲学博士；迪娜·弗林克哲学博士

Abstract 摘要

IMPORTANCE Current guidelines recommend a 28-day course of enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The high cost of this medication and the low adherence rates observed in prior studies provide an opportunity to benefit patients by demonstrating the safety of a more cost-effective, easier to use thromboprophylactic.
重要性现行指南推荐妇科恶性肿瘤术后使用 28 天疗程的依诺肝素进行血栓预防。该药物价格昂贵且既往研究显示患者依从性较低，因此通过验证更具成本效益、更易使用的血栓预防方案的安全性，可为患者带来获益。

OBJECTIVE To investigate the safety and efficacy of an oral treatment alternative for thromboprophylaxis in postoperative patients with gynecologic cancer.
目的探讨妇科肿瘤术后患者口服替代药物预防血栓的安全性和有效性。

DESIGN, SETTING, AND PARTICIPANTS This was a patient-based, multicenter, open-label, blinded, end point, randomized clinical trial conducted May 2015 to March 2019 in outpatient and inpatient gynecologic oncology settings. Women undergoing surgery for suspected or confirmed gynecologic cancer were approached for recruitment. The trial compared rates of major bleeding and clinically relevant nonmajor bleeding events during a 90-day follow-up period in patients taking apixaban or enoxaparin for postoperative thromboprophylaxis using a modified intent-to-treat analysis. Data analysis was performed from October to December 2019.
设计、场所与受试者本研究为基于患者的、多中心、开放标签、设盲终点的随机临床试验，于 2015 年 5 月至 2019 年 3 月在妇科肿瘤门诊及住院部开展。招募对象为疑似或确诊妇科肿瘤需接受手术治疗的女性患者。试验采用改良意向治疗分析法，比较术后使用阿哌沙班或依诺肝素进行血栓预防的患者在 90 天随访期内大出血及临床相关非大出血事件的发生率。数据分析时间为 2019 年 10 月至 12 月。

INTERVENTIONS Women were randomized to 28 days of apixaban ( 2.5 mg orally twice daily) or enoxaparin ( 40 mg subcutaneously daily).
干预措施受试者随机接受 28 天的阿哌沙班（口服 2.5mg，每日两次）或依诺肝素（皮下注射 40mg，每日一次）治疗。

MAIN OUTCOMES AND MEASURES The primary outcome was major bleeding and clinically relevant nonmajor bleeding events. Secondary outcomes included incidence of venous thromboembolic events, adverse events, medication adherence, participant quality of life, and medication satisfaction.
主要结局指标为大出血和具有临床意义的非大出血事件。次要结局包括静脉血栓栓塞事件发生率、不良事件、用药依从性、受试者生活质量及用药满意度。

RESULTS Of 500 women recruited for the study, 400 were enrolled and randomized (median age, 58.0 years; range, 18.0-89.0 years); 204 received apixaban and 196 received enoxaparin. Treatment groups did not differ in terms of race/ethnicity, cancer stage, or surgery modality (open vs robotic). There were no statistically significant differences between the apixaban and enoxaparin groups in terms of rates of major bleeding events ( 1 patient [

0.5 %

] vs 1 patient [

0.5 %

]; odds ratio [OR], 1.04; 95% CI, 0.07-16.76;

P > .99

), clinically relevant nonmajor bleeding events ( 12 patients [5.4%] vs 19 patients [9.7%]; OR, 1.88; 95% CI, 0.87-4.1;

P = .11

), venous thromboembolic events (2 patients

[1.0 %]

vs 3 patients [1.5%]; OR, 1.57; 95% CI, 0.26-9.50;

P = .68

), adverse events, medication adherence, or quality of life between the groups. Participant satisfaction was significantly greater in the apixaban group with regard to ease of taking the medication (186 patients [98.9%] vs 110
研究结果在招募的 500 名女性中，最终纳入 400 例并随机分组（中位年龄 58.0 岁；范围 18.0-89.0 岁），其中 204 例接受阿哌沙班治疗，196 例接受依诺肝素治疗。治疗组在种族/民族、癌症分期或手术方式（开放手术与机器人手术）方面无差异。阿哌沙班组与依诺肝素组在大出血事件发生率（1 例[0.5%] vs 1 例[0.5%]；比值比[OR]1.04；95%CI 0.07-16.76）、临床相关非大出血事件（12 例[5.4%] vs 19 例[9.7%]；OR 1.88；95%CI 0.87-4.1）、静脉血栓栓塞事件（2 例[1.0%] vs 3 例[1.5%]；OR 1.57；95%CI 0.26-9.50）、不良事件发生率、用药依从性或生活质量方面均无统计学显著差异。在用药便利性方面，阿哌沙班组患者满意度显著更高（186 例[98.9%] vs 110 例
(continued) （接上）

Key Points 关键要点

Question Is there an efficacious and safe oral treatment for thromboprophylaxis in postoperative patients with suspected gynecologic malignant neoplasms?
研究问题对于疑似妇科恶性肿瘤的术后患者，是否存在有效且安全的口服血栓预防治疗方案？

Findings This multicenter randomized clinical trial included 400 women randomized to either oral apixaban or subcutaneous enoxaparin. There were no differences between groups for rates of major bleeding (0.5% vs 0.5%), clinically relevant nonmajor bleeding (5.4% vs 9.7%), and venous thromboembolic events (1.0% vs 1.5%); although adherence rates did not differ, patients in the apixaban group reported increased ease and decreased pain associated with taking the medication.
研究结果这项多中心随机临床试验纳入了 400 名女性受试者，随机分配至口服阿哌沙班组或皮下注射依诺肝素组。两组在大出血发生率（0.5% vs 0.5%）、临床相关非大出血事件（5.4% vs 9.7%）及静脉血栓栓塞事件（1.0% vs 1.5%）方面均无显著差异；尽管用药依从性未见差异，但阿哌沙班组患者反馈服药过程更便捷且疼痛感更低。

Meaning These findings suggest that oral apixaban may offer a safe alternative to subcutaneous enoxaparin that is easier and less painful for patients to take.
研究意义这些发现表明，口服阿哌沙班可能成为皮下注射依诺肝素的安全替代方案，对患者而言用药更便捷且痛苦更小。

Visual Abstract 可视化摘要
Invited Commentary 特邀评论
Supplemental content 补充内容
Author affiliations and article information are listed at the end of this article.
作者隶属机构及文章信息列于文末

Abstract (continued) 摘要（续）
patients [58.8%]; OR, 0.06; 95% CI, 0.01-0.25;

P < .001

) and pain associated with taking the medication (4 patients [2.1%] vs 92 patients [49.2%]; OR, 9.20; 95% CI, 2.67-31.82;

P < .001

).
患者[58.8%]；比值比 0.06；95%置信区间 0.01-0.25；

P < .001

）以及服药相关疼痛（4 名患者[2.1%]对比 92 名患者[49.2%]；比值比 9.20；95%置信区间 2.67-31.82；

P < .001

）。

CONCLUSIONS AND RELEVANCE These findings suggest that oral apixaban is a potentially safe, less painful, and easier-to-take alternative to subcutaneous enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The efficacy of apixaban to prevent venous thromboembolic events is hypothesized as being equivalent.
结论与相关性这些研究结果表明，对于妇科癌症术后血栓预防，口服阿哌沙班可能是皮下注射依诺肝素的一种更安全、痛苦更少且更易服用的替代方案。据推测，阿哌沙班预防静脉血栓栓塞事件的疗效与依诺肝素相当。

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCTO2366871
临床试验注册号：ClinicalTrials.gov 标识符 NCTO2366871

JAMA Network Open. 2020;3(6):e207410. doi:10.1001/jamanetworkopen.2020.7410
《美国医学会杂志网络开放版》2020 年第 3 卷第 6 期 e207410 号 doi:10.1001/jamanetworkopen.2020.7410

Introduction 引言

Gynecologic cancers (uterine, ovarian, cervical, and vulvar) affect approximately 100000 women in the US each year.

^{1}

The standard of care for nearly all gynecologic cancers (early and advanced stage) remains aggressive surgical debulking with resection of all visible disease. The extent of surgical resection to microscopic disease remains the factor most significantly associated with overall survival, particularly with ovarian cancer.

^{2}

每年美国约有 10 万名女性罹患妇科癌症（子宫癌、卵巢癌、宫颈癌和外阴癌）。

^{1}

几乎所有妇科癌症（早期和晚期）的标准治疗方案仍是以根治性肿瘤减灭术为主，即切除所有肉眼可见病灶。手术对微观病灶的切除范围是与患者总生存期最显著相关的因素，尤其在卵巢癌治疗中更为突出。

^{2}

Although specific procedures vary by disease site, nearly all include hysterectomy, removal of adnexa, removal of lymphatic tissue (pelvic and para-aortic), peritoneal biopsies, and omentectomy. These debulking procedures are often aggressive, requiring extended operative times with patients immobile and in a lithotomy position. On average, ovarian cancer debulking procedures may take up to 5 hours to complete.

^{3}

In addition, patients with gynecologic cancer tend to have risk factors further predisposing them to surgical morbidity, such as obesity, metabolic syndromes (eg, diabetes, hypertension, and glucose intolerance), and sedentary lifestyles.

^{4}

尽管具体术式因病灶部位而异，但几乎都包括子宫切除术、附件切除、淋巴组织（盆腔和腹主动脉旁）清扫、腹膜活检以及大网膜切除。这些减灭手术通常创伤较大，需延长手术时间，患者需保持截石位静止状态。卵巢癌减灭术平均耗时可达 5 小时。

^{3}

此外，妇科癌症患者往往合并肥胖、代谢综合征（如糖尿病、高血压和糖耐量异常）及久坐生活方式等危险因素，这些因素会进一步增加其手术并发症风险。

^{4}

Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), remains one of the most lethal complications in women who undergo surgery for gynecologic cancer. Because gynecologic tumors growing within the pelvis involve lymphatic drainage in direct contact with lower extremity vessels, VTE rates are significantly higher in women with gynecologic cancer compared with other cancers.

^{5, 6}

Rates of DVT after gynecologic cancer have been reported as high as

26 %

in untreated women and as high as

9 %

for postoperative PE.

^{7}

Pulmonary embolism is associated with mortality, and death may occur in up to

18 %

20 %

of patients with this complication.

^{8}

In addition, there is a risk for major bleeding after gynecologic surgery given the extent of dissection often involved.

^{9}

静脉血栓栓塞症（VTE）包括深静脉血栓形成（DVT）和肺栓塞（PE），仍是妇科癌症手术患者最致命的并发症之一。由于盆腔内生长的妇科肿瘤会累及与下肢血管直接接触的淋巴引流系统，妇科癌症患者的 VTE 发生率显著高于其他癌症患者。据报告，未接受治疗的妇科癌症患者术后 DVT 发生率高达

26 %

，术后 PE 发生率可达

9 %

。肺栓塞与患者死亡率相关，出现该并发症的患者中死亡比例可能高达

18 %

至

20 %

。此外，妇科手术常涉及大面积组织剥离，存在术后大出血风险。

The cost to the health care system of VTE complications is quite high because these patients require extended anticoagulation therapy and surveillance for 6 months after treatment. If a second DVT or PE occurs, lifelong anticoagulation therapy is usually necessary. The extended anticoagulation therapy time adds both financial and resource strain to health care systems because additional monitoring and imaging are required for these women to ensure that VTE is not worsening. The American Society of Clinical Oncology has developed guidelines for postoperative VTE prophylaxis in oncology patients to reduce the health care burden of these complications.

^{10, 11}

These have been further validated with the adoption of the CHEST 2016 guidelines

^{12}

and include the use of preoperative heparin, sequential compression devices during surgery, and postsurgical DVT prophylaxis using heparin and low-molecular-weight heparin. Current recommendations include 28 days of postoperative prophylaxis with low-molecular-weight heparin (enoxaparin 40 mg subcutaneously daily).

^{13}

静脉血栓栓塞并发症对医疗系统造成的负担相当沉重，因为这些患者需要接受长达 6 个月的延长抗凝治疗及监测。若出现二次深静脉血栓或肺栓塞，通常需终身进行抗凝治疗。延长抗凝治疗时间不仅增加了医疗系统的财务压力，也加剧了资源消耗，因为需要对这些女性患者进行额外监测和影像检查，以确保静脉血栓栓塞病情未恶化。美国临床肿瘤学会已制定肿瘤患者术后静脉血栓栓塞预防指南，以减轻这类并发症带来的医疗负担。这些指南随着 2016 年 CHEST 指南的采用得到进一步验证，内容包括术前使用肝素、术中应用序贯加压装置，以及术后采用肝素和低分子量肝素预防深静脉血栓形成。现行建议包括术后连续 28 天使用低分子量肝素（依诺肝素 40 毫克每日皮下注射）进行预防性治疗。

For a variety of reasons, the use of subcutaneous low-molecular-weight heparin has not proven to be ideal. Although the drug has been associated with a decrease in VTE, its use has come into question. Common patient complaints related to low-molecular-weight heparin use include injection
由于多种原因，皮下注射低分子肝素的使用效果并不理想。虽然该药物能降低静脉血栓栓塞症（VTE）发生率，但其应用仍存在争议。患者使用低分子肝素后常见的不良反应包括注射部位反应、自行注射时的疼痛、淤青、出血、恶心呕吐以及治疗费用问题。
site reaction, pain with autoinjection, bruising, bleeding, nausea, vomiting, and cost. Although the rate of adherence to outpatient postoperative thromboprophylaxis in women with gynecologic cancers has not been elucidated, data from the orthopedics literature identified an adherence rate of only approximately

60 % .^{14}

With enoxaparin use in outpatient prophylaxis demonstrating poor adherence, a more cost-effective and easier to use medication could affect VTE outcomes. Oral anticoagulation therapy could obviate many of the negative effects associated with the subcutaneous route of administration.
尽管妇科肿瘤患者术后门诊血栓预防的依从性数据尚未明确，但骨科文献资料显示其依从率仅约@0%。依诺肝素用于门诊预防时表现出较差的用药依从性，因此更具成本效益且更易使用的药物可能改善 VTE 预后。口服抗凝疗法可避免许多皮下给药途径带来的负面影响。

Apixaban, an oral factor Xa antagonist, has been studied in the prevention of VTE for patients undergoing hip and knee replacement surgery.

^{15 - 17}

The safety and effectiveness of apixaban compared with enoxaparin and with placebo have been demonstrated as a prophylaxis in surgical patients and in patients for recurrence of VTE. High-risk patients with cancer (approximately 2%) in the ambulatory settings were also assessed.

^{18, 19}

However, to our knowledge, apixaban has not been investigated for VTE prophylaxis in patients undergoing abdominal surgery with laparotomy or in patients with gynecologic cancers. Given the similar risk profile for postsurgical VTE in patients with gynecologic cancers, the aim of this investigation was to determine the safety (ie, rates of major bleeding and clinically relevant nonmajor [CRNM] bleeding) of apixaban use in women undergoing surgery for suspected gynecologic cancer. Secondary objectives included assessing efficacy in preventing VTE.
阿哌沙班作为一种口服 Xa 因子抑制剂，已被研究用于髋膝关节置换术患者预防静脉血栓栓塞症(VTE)。

^{15 - 17}

研究证实，与依诺肝素和安慰剂相比，阿哌沙班在外科手术患者及预防 VTE 复发患者中具有安全有效的预防作用。同时评估了门诊环境中约 2%的高危癌症患者。

^{18, 19}

但据我们所知，目前尚未研究阿哌沙班在开腹手术患者或妇科癌症患者中预防 VTE 的效果。鉴于妇科癌症患者术后 VTE 风险特征相似，本研究旨在评估疑似妇科癌症手术女性使用阿哌沙班的安全性（即大出血和临床相关非大出血[CRNM]发生率）。次要目标包括评估预防 VTE 的疗效。

Methods 研究方法

Study Design and Oversight
研究设计与监管

This trial was a multicenter, prospective, randomized, open-blinded, end point clinical trial conducted at the University of Colorado Hospital in Aurora and University of Southern California, Keck School of Medicine-Hospital in Los Angeles. Because of the difference in mode of delivery (injection vs oral) and the surgical nature of the study population, it was not possible to blind the investigators to the intervention. Patients were approached in the perioperative period, and informed written consent was obtained with institutional review board approval from both institutions. The protocol is outlined in Supplement 1 and the eFigure in Supplement 2. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
该试验是一项多中心、前瞻性、随机、开放标签的终点临床试验，在奥罗拉市科罗拉多大学医院和洛杉矶南加州大学凯克医学院附属医院开展。由于给药方式（注射与口服）的差异以及研究人群的手术性质，研究者无法对干预措施实施盲法。患者在围手术期被纳入研究，并获得两家机构伦理审查委员会批准的书面知情同意书。研究方案详见补充材料 1 及补充材料 2 中的电子图表。本研究遵循临床试验报告统一标准（CONSORT）报告规范。

Per accepted standards, participants were recommended to receive heparin (5000 subcutaneous units) 30 minutes before incision, as well as pneumatic compression devices during surgery and during postoperative hospitalization. Postsurgical care included 5000 subcutaneous units of heparin 3 times per day on the first postoperative day until patients were deemed safe for randomization by the operating surgeon. If epidural anesthesia was used, randomization occurred 8 hours after removal of the catheter. Participants were randomly assigned in a 1:1 ratio to oral apixaban ( 2.5 mg twice daily) for 28 days or subcutaneous enoxaparin ( 40 mg daily) for 28 days. Randomization was performed by the inpatient pharmacist at the University of Colorado Hospital, who was impartial to all other aspects of the study, using an online randomizer.

^{20}

Patients were evaluated on study day 1 (the day of the first dose), day 14 (

\pm 4

days), day 28 (

\pm 4

days), and day 90

(\pm 14

days

)

, to assess for the primary and secondary outcomes. Adherence to medication regimen was monitored by participant report, study diary, and assessment of pill bottles or syringes. Participants were deemed adherent with medication if they missed 2 days or fewer of treatment over the course of 28 days (ie, <4 pills or <2 injections missed). The University of Colorado Cancer Center’s Data Safety Monitoring board conducted regular review of the ongoing trial for patient safety and study adherence. An independent blinded reviewer (an oncologist not associated with the trial) conducted assessments of all major and CRNM bleeding events.
根据公认标准，建议参与者在切口前 30 分钟接受肝素（5000 单位皮下注射），并在手术期间及术后住院期间使用气压压缩装置。术后护理包括术后第一天每日三次皮下注射 5000 单位肝素，直至主刀医师认为患者可安全进行随机分组。若采用硬膜外麻醉，则需在导管拔除 8 小时后进行随机分组。参与者按 1:1 比例随机分配至口服阿哌沙班组（2.5 毫克每日两次，持续 28 天）或皮下注射依诺肝素组（40 毫克每日一次，持续 28 天）。随机分组由科罗拉多大学医院住院药师通过在线随机系统完成，该药师不参与研究的其他环节。患者在研究第 1 天（首次给药日）、第 14 天（

\pm 4

天）、第 28 天（

\pm 4

天）和第 90 天（

(\pm 14

天

)

）接受评估以监测主要和次要结局指标。通过参与者自述、研究日记及药瓶/注射器核查来监测用药依从性。若参与者在 28 天疗程中漏服药物不超过 2 天（即漏服<4 片药或<2 次注射），则被视为服药依从性良好。科罗拉多大学癌症中心数据安全监测委员会定期审查该持续试验的患者安全性与研究依从性。所有大出血及临床相关非大出血事件均由一位独立盲审员（未参与试验的肿瘤科医师）进行评估。

Study Population 研究人群

All patients with a suspected or confirmed diagnosis of gynecologic cancer and who underwent surgery, either by laparotomy or laparoscopy, were eligible for enrollment. Patients with suspected
所有疑似或确诊妇科恶性肿瘤并接受开腹或腹腔镜手术的患者均符合入组条件。疑似患者
gynecologic cancer included those with a pelvic mass, precancerous lesions of the gynecologic tract, an elevated serum cancer antigen 125 level, and vulvar or cervical lesions. Patients with confirmed gynecologic cancer included those with histologic diagnosis confirmed by pathologic review of an ovarian, uterine, cervical, or vulvar cancer. Women aged 18 to 89 years at 1 of the participating gynecologic cancer centers during the enrollment period who were deemed medically fit for surgery and who were able to return for the 90-day follow-up were included. Race/ethnicity was collected from electronic medical records. This was assessed to be included in the demographic characteristics and to see a broad applicability to the study population. Exclusion criteria included a confirmed pathologic diagnosis other than gynecologic cancer before surgery, known history of VTE, long-term use of nonsteroidal anti-inflammatory drugs, concurrent use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, history of severe renal or hepatic disease, known diagnosis of bleeding dyscrasia (eg, von Willebrand disease), or history of disorders that predispose to hypercoagulability (eg, Factor V Leiden homozygotes or antithrombin deficiency).
妇科癌症患者包括存在盆腔肿块、妇科癌前病变、血清癌抗原 125 水平升高以及外阴或宫颈病变的患者。确诊的妇科癌症患者需经病理学检查确认患有卵巢癌、子宫癌、宫颈癌或外阴癌。研究纳入标准为：在参与研究的妇科癌症中心就诊期间年龄 18 至 89 岁、经评估适合接受手术治疗且能完成 90 天随访的女性患者。种族/民族信息从电子病历中采集，该数据用于纳入人口学特征分析，以验证研究结果对广泛人群的适用性。排除标准包括术前确诊为非妇科癌症的病理诊断、已知静脉血栓栓塞病史、长期使用非甾体抗炎药、同时使用选择性 5-羟色胺再摄取抑制剂或 5-羟色胺-去甲肾上腺素再摄取抑制剂、严重肝肾疾病史、已知出血性疾病诊断（如血管性血友病）、或存在易导致高凝状态的疾病史（如纯合子因子 V Leiden 突变或抗凝血酶缺乏症）。

Study Outcomes 研究结果

The primary end point of this study was the incidence of major bleeding and CRNM bleeding events occurring during the treatment phase and in the 30 days after treatment. Secondary end points included incidence of VTE outcomes during treatment and in the 60-day posttreatment period, medication adherence rates, quality of life, and satisfaction of use for oral apixaban compared with subcutaneous enoxaparin.
本研究主要终点为治疗期间及治疗后 30 天内发生的大出血和临床相关非大出血事件发生率。次要终点包括治疗期间及治疗后 60 天内静脉血栓栓塞结局发生率、用药依从率、生活质量评估，以及口服阿哌沙班相较皮下注射依诺肝素的使用满意度。

Major bleeding was defined according to International Society on Thrombosis and Hemostasis criteria,

^{21}

including fatal bleeding and/or symptomatic bleeding in a critical area or organ (eg, intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome) or bleeding requiring the transfusion of 2 units of packed red blood cells. Clinically relevant nonmajor bleeding events were defined as events that did not meet the definition of major bleeding but were associated with medical intervention, unscheduled contact with a physician, temporary cessation of drug therapy, or any other discomfort, such as pain or impairment of activities of daily life.
主要出血事件根据国际血栓与止血学会标准定义，包括致命性出血和/或关键部位或器官（如颅内、椎管内、眼内、腹膜后、关节内、心包或伴有筋膜室综合征的肌内）的症状性出血，或需要输注 2 单位浓缩红细胞的出血。临床相关非主要出血事件定义为不符合主要出血标准但需医疗干预、非计划性就医、暂停药物治疗或导致其他不适（如疼痛或日常生活能力受损）的出血情况。

Screening for VTE was done by the study investigator using the Wells criteria for DVT assessment tool

^{22}

at 14,28 , and 90 days after surgery or if standard symptoms developed (eg, unilateral leg swelling, dyspnea, or tachycardia). All participants generally met the criteria for moderate risk by satisfying the Wells criteria of having an active cancer and undergoing major surgery within 4 weeks; therefore, we did not further screen participants only meeting a moderate risk. Participants meeting the criteria for high probability of DVT per the Wells criteria were confirmed by venous Doppler ultrasonography. Determination of suspected PE was measured using additional risk criteria adapted from the Wells criteria modified for PE tool and confirmed by chest computed tomography for those meeting the criteria for high risk.

^{23}

研究调查员采用 Wells 深静脉血栓评估标准工具

^{22}

，在术后第 14、28 和 90 天或出现标准症状（如单侧腿部肿胀、呼吸困难或心动过速）时进行静脉血栓栓塞筛查。所有受试者因满足"活动性癌症"和"4 周内接受大手术"这两项 Wells 标准，基本符合中度风险标准；因此我们未对仅符合中度风险的受试者进行进一步筛查。根据 Wells 标准判定为深静脉血栓高概率的受试者，需经静脉多普勒超声检查确诊。疑似肺栓塞的判定采用基于 Wells 标准改良的肺栓塞评估工具中的附加风险标准，对符合高风险标准的受试者通过胸部计算机断层扫描确诊。

^{23}

Additional secondary analysis included quality of life, compliance, and satisfaction. Quality of life was evaluated using the validated SF-8 health survey provided by Optum,

^{24}

which measured overall physical and mental well-being at baseline and end of treatment. Satisfaction was assessed using a participant questionnaire.

^{25}

Difficulty remembering to take medication, pain associated with medication, and medication ease of use were measured. Adverse events were graded using the Common Terminology Criteria for Adverse Events system version 4.0.

^{26}

次要分析还包括生活质量、依从性和满意度评估。生活质量采用 Optum 公司提供的标准化 SF-8 健康调查量表进行测评，该量表在治疗开始和结束时分别对整体生理健康与心理健康状况进行评估。满意度通过参与者问卷进行测定。研究测量了服药记忆难度、药物相关疼痛以及用药便捷性等指标。不良事件采用 4.0 版不良事件通用术语标准进行分级。

Statistical Analysis 统计分析

A modified intent-to-treat analysis was based on participants initially assigned medication for the first day of treatment. Nonparametric medians tests or

t

tests were used to compare continuous variables. Fisher exact tests or

χ^{2}

tests were used to compare categorical or dichotomous variables. Descriptive statistics including tests for normality for continuous variables were computed. For all values, 2 -sided

P < .05

was considered statistically significant. SPSS statistical software version 26
改良意向治疗分析基于治疗首日最初分配药物的参与者。连续变量比较采用非参数中位数检验或卡方检验。分类或二分变量比较采用 Fisher 精确检验或卡方检验。计算了包括连续变量正态性检验在内的描述性统计量。所有检验均采用双侧检验，P 值<0.05 视为具有统计学意义。使用 SPSS 统计软件 26 版进行分析。
(IBM Corp) was used to perform all calculations. Data analysis was performed from October to December 2019.
所有计算均使用(IBM Corp)完成。数据分析于 2019 年 10 月至 12 月进行。

A previous study

^{27}

found an incidence of major bleeding of approximately

5 %

for the current standard of care (enoxaparin) vs a mean of

3.5 %

risk of major bleeding associated with apixaban treatment in patients undergoing hip or knee surgery. However, to our knowledge, data are not available for laparotomy or oncologic patients. Given that this population mainly underwent laparotomy, we estimated a slightly increased risk for bleeding in this safety evaluation. Thus, we estimated an

8 %

rate of major bleeding in the enoxaparin group. With 400 patients enrolled and

80 %

power with 2 -sided

a = .05

, we would be able to detect a difference of 6 percentage points, or

2 %

in the apixaban group. This

2 %

rate is clinically reasonable because we anticipated a higher rate of compliance in that group.
先前一项研究

^{27}

发现，当前标准治疗（依诺肝素）在大出血方面的发生率约为

5 %

，而接受髋关节或膝关节手术的患者使用阿哌沙班治疗的平均大出血风险为

3.5 %

。然而据我们所知，目前尚无针对剖腹手术或肿瘤患者的相关数据。鉴于本研究人群主要接受剖腹手术，我们在此安全性评估中预估其出血风险会略有增加。因此，我们估算依诺肝素组的大出血发生率为

8 %

。在纳入 400 例患者且检验效能为

80 %

（双侧

a = .05

）的情况下，我们能够检测出阿哌沙班组 6 个百分点（即

2 %

）的差异。这一

2 %

发生率具有临床合理性，因为我们预期该组的治疗依从性会更高。

Results 结果

Between May 2015 and March 2019, a total of 500 patients were approached for participation; 50 did not meet the inclusion criteria and 50 consented but failed the screening and did not undergo randomization because of surgeon discretion, patient preference, inability to follow-up, or immediate postoperative complication. Thus, 400 patients were enrolled into the study and included in the final analysis; 204 received apixaban and 196 received enoxaparin (Figure). The median age was 58.0 years (range, 18.0-89.0 years); 322 women (

80.5 %

) were non-Hispanic white, 158 women (

39.5 %

) had high-stage cancer (stages III and IV), and 317 women (79.3%) underwent open vs robotic surgery. The demographic data did not differ between the 2 treatment groups: for the apixaban group vs the enoxaparin group, the median age was 58.0 years (range,

21.0 - 87.0

years) vs 58.5 years (18.0-89.0 years), 158 patients (77.5%) vs 164 patients (83.7%) were non-Hispanic white, 84 patients (

41.2 %

) vs 74 patients (

37.8 %

) had high-stage cancer, 165 patients (

80.9 %

) vs 152 patients (

77.6 %

) underwent open surgery, 164 patients (

80.4 %

) vs 159 patients (

81.1 %

) had true cancer diagnoses, and the median body mass index (calculated as weight in kilograms divided by height in meters squared) was 27.4 (range, 11.0-50.5) vs 26.5 (range, 15.8-57.2) (Table 1).
2015 年 5 月至 2019 年 3 月期间，共有 500 名患者被纳入参与研究；其中 50 人不符合入选标准，另有 50 人同意参与但未通过筛查且未进行随机分组，原因包括外科医生判断、患者意愿、无法随访或术后即刻并发症。因此，最终 400 名患者被纳入研究并参与最终分析；其中 204 人接受阿哌沙班治疗，196 人接受依诺肝素治疗（见图表）。患者中位年龄为 58.0 岁（范围 18.0-89.0 岁）；322 名女性（

80.5 %

）为非西班牙裔白人，158 名女性（

39.5 %

）患有高分期癌症（III 期和 IV 期），317 名女性（79.3%）接受开腹手术而非机器人手术。两组治疗人群的人口统计学数据无显著差异：阿哌沙班组与依诺肝素组相比，中位年龄为 58.0 岁（范围

21.0 - 87.0

岁）对比 58.5 岁（18.0-89.0 岁），非西班牙裔白人患者分别为 158 例（77.5%）对比 164 例（83.7%），晚期癌症患者 84 例（

41.2 %

）对比 74 例（

37.8 %

），接受开放手术患者 165 例（

80.9 %

）对比 152 例（

77.6 %

），确诊恶性肿瘤患者 164 例（

80.4 %

）对比 159 例（

81.1 %

），中位体重指数（按体重公斤数除以身高米数平方计算）为 27.4（范围 11.0-50.5）对比 26.5（范围 15.8-57.2）（表 1）。

Figure. Enrollment, Randomization, and Follow-up
图. 入组、随机化和随访情况

Flow diagram shows identification of cohort of women who underwent surgical procedures for gynecologic cancers and who were enrolled and treated in the study.
流程图展示了接受妇科癌症手术治疗并参与本研究的女性的队列筛选过程。

The attrition rates were 3.8% (15 of 400 patients) at the 28-day study visit and 17.3% (69 of 400 patients) at the 90 -day study visit. Attrition occurred as the result of major bleeding (2 patients), VTE (5 patients), medication nonadherence (10 patients), withdrawal from study by the participant (21 patients) or investigator (6 patients), hospitalization (19 patients), hospice admission
28 天研究访视时的失访率为 3.8%（400 例患者中的 15 例），90 天研究访视时的失访率为 17.3%（400 例患者中的 69 例）。失访原因包括大出血（2 例患者）、静脉血栓栓塞（5 例患者）、用药依从性差（10 例患者）、受试者自行退出研究（21 例患者）或研究者决定退出（6 例患者）、住院治疗（19 例患者）、入住临终关怀机构

Table 1. Baseline Characteristics of Participants
表 1. 受试者基线特征

Characteristic 特征	Participants, No. (%) 参与者人数（占比）			OR (95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Characteristic 特征	Apixaban ( $n = 204$ ) 阿哌沙班（ $n = 204$ ）	Enoxaparin ( $n = 196$ ) 依诺肝素（ $n = 196$ ）	Total ( $N = 400$ ) 总计（ $N = 400$ ）	OR (95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Age, median (range), y 年龄，中位数（范围），岁	58.0 (21.0-87.0)	58.5 (18.0-89.0)	58.0 (18.0-89.0)	NA	. 30
Body mass index, median (range) $^{a}$ 体重指数，中位数（范围） $^{a}$	27.4 (11.0-50.5)	26.5 (15.8-57.2)	27.0 (11.0-57.2)	NA	. 26
Race/ethnicity 种族/民族
White 白人	158 (77.5)	164 (83.7)	322 (80.5)	NA	. 29
Hispanic 西班牙裔	38 (18.6)	23 (11.7)	61 (15.3)
African American 非裔美国人	5 (2.5)	6 (3.1)	11 (2.8)
Asian 亚裔	3 (1.5)	3 (1.5)	6 (1.5)
Suspected cancer site 疑似癌症部位
Uterine 子宫	81 (39.7)	83 (42.3)	164 (41.0)	NA	. 94
Ovarian or fallopian 卵巢或输卵管	90 (44.1)	78 (39.8)	168 (42.0)
Cervical 宫颈	20 (9.8)	22 (11.2)	42 (10.5)
Vulvar or vaginal 外阴或阴道	7 (3.4)	7 (3.6)	14 (3.5)
Other 其他	6 (2.9)	6 (3.1)	12 (3.0)
Surgical intervention 手术干预
Open 开放	165 (80.9)	152 (77.6)	317 (79.3)	0.82 (0.50-1.33)	. 41
Minimally invasive 微创	39 (19.1)	44 (22.4)	83 (20.8)	0.82 (0.50-1.33)	. 41
Surgical procedure 手术操作
Total abdominal hysterectomy 全腹式子宫切除术
With bilateral or unilateral salpingo-oophorectomy 伴双侧或单侧输卵管卵巢切除术	116 (56.9)	112 (57.1)	228 (57.0)	1.01 (0.68-1.50)	. 96
Without ovaries 无卵巢	5 (2.5)	3 (1.5)	8 (2.0)	0.62 (0.15-2.62)	. 51
Bilateral or unilateral salpingo-oophorectomy (no total abdominal hysterectomy) 双侧或单侧输卵管卵巢切除术（未行全子宫切除术）	42 (20.6)	49 (25.0)	91 (22.8)	1.29 (0.81-2.06)	. 29
Radical hysterectomy 根治性子宫切除术	18 (8.8)	24 (12.2)	42 (10.5)	1.44 (0.76-2.75)	. 26
Lymph node dissection 淋巴结清扫术	93 (45.6)	88 (44.9)	181 (45.3)	0.97 (0.66-1.44)	. 89
Bowel resection 肠切除手术	25 (12.3)	12 (6.1)	37 (9.3)	0.47 (0.23-0.96)	. 03
Removal of omentum 网膜切除术	82 (40.2)	82 (41.8)	164 (41.0)	1.07 (0.72-1.59)	. 74
Surgical complications 手术并发症	15 (7.4)	10 (5.1)	25 (6.3)	0.67 (0.30-1.54)	. 35
Duration of surgery, median (range), min 手术时长，中位数（范围），分钟	204 (31-600)	215.5 (17-743)	209 (17-743)	NA	. 30
Confirmed diagnosis 确诊诊断
Malignant or borderline 恶性或交界性	164 (80.4)	159 (81.1)	323 (80.8)	1.06 (0.64-1.73)	. 83
Benign 良性	40 (19.6)	37 (18.8)	77 (19.3)	1.06 (0.64-1.73)	. 83
Confirmed site of origin $^{b}$ 确认原发部位 $^{b}$
Patients, No. 患者编号	164	159	323	NA	. 43
Uterine 子宫	65 (31.9)	63 (32.1)	128 (32.0)
Ovarian or fallopian 卵巢或输卵管	77 (37.7)	64 (32.7)	141 (35.5)
Cervical 宫颈	12 (5.9)	18 (9.2)	30 (7.5)
Vulvar or vaginal 外阴或阴道	6 (2.9)	7 (3.6)	13 (3.3)
Other 其他	4 (2.0)	7 (3.6)	11 (2.8)
Stage $^{b}$ 分期 $^{b}$
Low (I or II) 低度（I 或 II 级）	80 (39.2)	85 (43.4)	165 (41.3)	1.14 (0.73-1.76)	. 57
High (III or IV) 高级别（III 或 IV 级）	84 (41.2)	74 (37.8)	158 (39.5)	1.14 (0.73-1.76)	. 57

Characteristic Participants, No. (%) OR (95% CI) P value Apixaban ( n=204 ) Enoxaparin ( n=196 ) Total ( N=400 ) Age, median (range), y 58.0 (21.0-87.0) 58.5 (18.0-89.0) 58.0 (18.0-89.0) NA . 30 Body mass index, median (range) ^("a ") 27.4 (11.0-50.5) 26.5 (15.8-57.2) 27.0 (11.0-57.2) NA . 26 Race/ethnicity White 158 (77.5) 164 (83.7) 322 (80.5) NA . 29 Hispanic 38 (18.6) 23 (11.7) 61 (15.3) African American 5 (2.5) 6 (3.1) 11 (2.8) Asian 3 (1.5) 3 (1.5) 6 (1.5) Suspected cancer site Uterine 81 (39.7) 83 (42.3) 164 (41.0) NA . 94 Ovarian or fallopian 90 (44.1) 78 (39.8) 168 (42.0) Cervical 20 (9.8) 22 (11.2) 42 (10.5) Vulvar or vaginal 7 (3.4) 7 (3.6) 14 (3.5) Other 6 (2.9) 6 (3.1) 12 (3.0) Surgical intervention Open 165 (80.9) 152 (77.6) 317 (79.3) 0.82 (0.50-1.33) . 41 Minimally invasive 39 (19.1) 44 (22.4) 83 (20.8) Surgical procedure Total abdominal hysterectomy With bilateral or unilateral salpingo-oophorectomy 116 (56.9) 112 (57.1) 228 (57.0) 1.01 (0.68-1.50) . 96 Without ovaries 5 (2.5) 3 (1.5) 8 (2.0) 0.62 (0.15-2.62) . 51 Bilateral or unilateral salpingo-oophorectomy (no total abdominal hysterectomy) 42 (20.6) 49 (25.0) 91 (22.8) 1.29 (0.81-2.06) . 29 Radical hysterectomy 18 (8.8) 24 (12.2) 42 (10.5) 1.44 (0.76-2.75) . 26 Lymph node dissection 93 (45.6) 88 (44.9) 181 (45.3) 0.97 (0.66-1.44) . 89 Bowel resection 25 (12.3) 12 (6.1) 37 (9.3) 0.47 (0.23-0.96) . 03 Removal of omentum 82 (40.2) 82 (41.8) 164 (41.0) 1.07 (0.72-1.59) . 74 Surgical complications 15 (7.4) 10 (5.1) 25 (6.3) 0.67 (0.30-1.54) . 35 Duration of surgery, median (range), min 204 (31-600) 215.5 (17-743) 209 (17-743) NA . 30 Confirmed diagnosis Malignant or borderline 164 (80.4) 159 (81.1) 323 (80.8) 1.06 (0.64-1.73) . 83 Benign 40 (19.6) 37 (18.8) 77 (19.3) Confirmed site of origin ^("b ") Patients, No. 164 159 323 NA . 43 Uterine 65 (31.9) 63 (32.1) 128 (32.0) Ovarian or fallopian 77 (37.7) 64 (32.7) 141 (35.5) Cervical 12 (5.9) 18 (9.2) 30 (7.5) Vulvar or vaginal 6 (2.9) 7 (3.6) 13 (3.3) Other 4 (2.0) 7 (3.6) 11 (2.8) Stage ^("b ") Low (I or II) 80 (39.2) 85 (43.4) 165 (41.3) 1.14 (0.73-1.76) . 57 High (III or IV) 84 (41.2) 74 (37.8) 158 (39.5)

| Characteristic | Participants, No. (%) | | | OR (95% CI) | $P$ value | | :--- | :--- | :--- | :--- | :--- | :--- | | | Apixaban ( $\mathrm{n}=204$ ) | Enoxaparin ( $\mathrm{n}=196$ ) | Total ( $\mathrm{N}=400$ ) | | | | Age, median (range), y | 58.0 (21.0-87.0) | 58.5 (18.0-89.0) | 58.0 (18.0-89.0) | NA | . 30 | | Body mass index, median (range) ${ }^{\text {a }}$ | 27.4 (11.0-50.5) | 26.5 (15.8-57.2) | 27.0 (11.0-57.2) | NA | . 26 | | Race/ethnicity | | | | | | | White | 158 (77.5) | 164 (83.7) | 322 (80.5) | NA | . 29 | | Hispanic | 38 (18.6) | 23 (11.7) | 61 (15.3) | | | | African American | 5 (2.5) | 6 (3.1) | 11 (2.8) | | | | Asian | 3 (1.5) | 3 (1.5) | 6 (1.5) | | | | Suspected cancer site | | | | | | | Uterine | 81 (39.7) | 83 (42.3) | 164 (41.0) | NA | . 94 | | Ovarian or fallopian | 90 (44.1) | 78 (39.8) | 168 (42.0) | | | | Cervical | 20 (9.8) | 22 (11.2) | 42 (10.5) | | | | Vulvar or vaginal | 7 (3.4) | 7 (3.6) | 14 (3.5) | | | | Other | 6 (2.9) | 6 (3.1) | 12 (3.0) | | | | Surgical intervention | | | | | | | Open | 165 (80.9) | 152 (77.6) | 317 (79.3) | 0.82 (0.50-1.33) | . 41 | | Minimally invasive | 39 (19.1) | 44 (22.4) | 83 (20.8) | | | | Surgical procedure | | | | | | | Total abdominal hysterectomy | | | | | | | With bilateral or unilateral salpingo-oophorectomy | 116 (56.9) | 112 (57.1) | 228 (57.0) | 1.01 (0.68-1.50) | . 96 | | Without ovaries | 5 (2.5) | 3 (1.5) | 8 (2.0) | 0.62 (0.15-2.62) | . 51 | | Bilateral or unilateral salpingo-oophorectomy (no total abdominal hysterectomy) | 42 (20.6) | 49 (25.0) | 91 (22.8) | 1.29 (0.81-2.06) | . 29 | | Radical hysterectomy | 18 (8.8) | 24 (12.2) | 42 (10.5) | 1.44 (0.76-2.75) | . 26 | | Lymph node dissection | 93 (45.6) | 88 (44.9) | 181 (45.3) | 0.97 (0.66-1.44) | . 89 | | Bowel resection | 25 (12.3) | 12 (6.1) | 37 (9.3) | 0.47 (0.23-0.96) | . 03 | | Removal of omentum | 82 (40.2) | 82 (41.8) | 164 (41.0) | 1.07 (0.72-1.59) | . 74 | | Surgical complications | 15 (7.4) | 10 (5.1) | 25 (6.3) | 0.67 (0.30-1.54) | . 35 | | Duration of surgery, median (range), min | 204 (31-600) | 215.5 (17-743) | 209 (17-743) | NA | . 30 | | Confirmed diagnosis | | | | | | | Malignant or borderline | 164 (80.4) | 159 (81.1) | 323 (80.8) | 1.06 (0.64-1.73) | . 83 | | Benign | 40 (19.6) | 37 (18.8) | 77 (19.3) | | | | Confirmed site of origin ${ }^{\text {b }}$ | | | | | | | Patients, No. | 164 | 159 | 323 | NA | . 43 | | Uterine | 65 (31.9) | 63 (32.1) | 128 (32.0) | | | | Ovarian or fallopian | 77 (37.7) | 64 (32.7) | 141 (35.5) | | | | Cervical | 12 (5.9) | 18 (9.2) | 30 (7.5) | | | | Vulvar or vaginal | 6 (2.9) | 7 (3.6) | 13 (3.3) | | | | Other | 4 (2.0) | 7 (3.6) | 11 (2.8) | | | | Stage ${ }^{\text {b }}$ | | | | | | | Low (I or II) | 80 (39.2) | 85 (43.4) | 165 (41.3) | 1.14 (0.73-1.76) | . 57 | | High (III or IV) | 84 (41.2) | 74 (37.8) | 158 (39.5) | | |

Abbreviations: NA, not applicable; OR, odds ratio.
缩写：NA，不适用；OR，比值比。

^{a}

Body mass index is calculated as weight in kilograms divided by height in meters squared.

^{a}

体重指数计算公式为体重（千克）除以身高（米）的平方。

^{b}

Excludes patients with benign neoplasm.

^{b}

排除良性肿瘤患者。
(1 patient), and death (4 patients). No patient deaths were associated with the study medication, with 2 deaths as a result of sepsis and 2 as a result of disease progression.
（1 例患者）和死亡（4 例患者）。无患者死亡与研究药物相关，其中 2 例死亡由败血症导致，2 例由疾病进展导致。

Major bleeding occurred in 1 participant in the apixaban group and 1 in the enoxaparin group (

0.5 %

0.5 %

; odds ratio [OR], 1.04;

95 % Cl, 0.07 - 16.76; P > .99

) (Table 2). Both patients required blood transfusions, recovered after discontinuation of drug, and had events Common Terminology Criteria for Adverse Events grade 3. Clinically relevant nonmajor bleeding events (hematoma, bruising, epistaxis, and vaginal bleeding) were similar between groups ( 12 patients in the apixaban group [5.4%] vs 19 patients in the enoxaparin group [9.7%]; OR, 1.88; 95% CI, 0.87-4.1;

P = .11

) (Table 2). As a composite of both major and CRNM bleeding events, there was no difference between the apixaban and enoxaparin groups (OR,

1.67; 95 % Cl, 0.81 - 3.56; P = .16

). During the 90 -day follow-up period, a total of 11 participants (

2.8 %

) met the high-risk Wells criteria for suspicion of VTE and underwent lower extremity ultrasonography or chest computed tomography angiography. Five participants had VTE (2 in the apixaban group [1.0%] vs 3 in the enoxaparin group [1.5%]; OR, 1.57;

95 % Cl, 0.26 - 9.50; P = .68

) (Table 2 and eTable 1 in Supplement 2). All participants with confirmed VTE were removed from the study and were prescribed treatment with enoxaparin (

1 mg / kg

twice daily) for 6 months.
阿哌沙班组和依诺肝素组各有 1 例患者发生大出血（

0.5 %

0.5 %

；比值比[OR]1.04；

95 % Cl, 0.07 - 16.76; P > .99

）（表 2）。两名患者均需输血治疗，停药后恢复，不良事件均达到通用不良事件术语标准 3 级。临床相关非大出血事件（血肿、瘀斑、鼻出血和阴道出血）在两组间发生率相似（阿哌沙班组 12 例[5.4%] vs 依诺肝素组 19 例[9.7%]；OR 1.88；95%CI 0.87-4.1；

P = .11

）（表 2）。综合大出血与临床相关非大出血事件，两组间无显著差异（OR

1.67; 95 % Cl, 0.81 - 3.56; P = .16

）。在 90 天随访期内，共 11 名受试者（

2.8 %

）符合 VTE 高危 Wells 标准并接受下肢超声或胸部 CT 血管造影检查。其中 5 例确诊 VTE（阿哌沙班组 2 例[1.0%] vs 依诺肝素组 3 例[1.5%]；OR 1.57；

95 % Cl, 0.26 - 9.50; P = .68

）（表 2 及补充材料 2 中 eTable1）。所有确诊静脉血栓栓塞（VTE）的参与者均被移出研究，并接受为期 6 个月的依诺肝素治疗（每日两次

1 mg / kg

）。

Adverse events attributable to the study medications were similar between both groups of this investigation with regard to the most common events: for the apixaban group vs the enoxaparin group, 6 patients (

2.9 %

) vs 5 patients (

2.6 %

) were hospitalized within 28 days after surgery, 7 patients (3.4%) vs 10 patients (5.1%) had wound infection, 1 patient (0.5%) vs 5 patients (2.6%) had hematoma, 1 patient each (0.5%) had suspected allergic reaction, 4 patients (2.0%) vs 11 patients (5.6%) had bruising, 7 patients (3.4%) vs 2 patients (1.0%) had arthralgia, 1 patient (0.5%) vs 2 patients (1.0%) had rash, 3 patients (1.5%) vs 2 patients (1.0%) had epistaxis, and 7 patients (3.4%) vs 5 patients (

2.6 %

) had headache (Table 3). More participants in the apixaban group experienced dizziness compared with the enoxaparin group ( 10 patients [4.9%] vs 1 patient [0.5%]; OR, O.10;
本研究两组药物相关不良事件发生率在常见症状方面相似：阿哌沙班组 vs 依诺肝素组，术后 28 天内住院患者分别为 6 例（

2.9 %

）vs 5 例（

2.6 %

），伤口感染 7 例（3.4%）vs 10 例（5.1%），血肿 1 例（0.5%）vs 5 例（2.6%），疑似过敏反应各 1 例（0.5%），瘀斑 4 例（2.0%）vs 11 例（5.6%），关节痛 7 例（3.4%）vs 2 例（1.0%），皮疹 1 例（0.5%）vs 2 例（1.0%），鼻出血 3 例（1.5%）vs 2 例（1.0%），头痛 7 例（3.4%）vs 5 例（

2.6 %

）（表 3）。阿哌沙班组头晕发生率高于依诺肝素组（10 例[4.9%] vs 1 例[0.5%]；OR 值 0.10；

Table 2. Primary and Secondary Outcomes: Major Bleeding, Clinically Relevant Nonmajor Bleeding, and Venous Thromboembolic Events
表 2. 主要与次要结局：大出血、临床相关非大出血及静脉血栓栓塞事件

Event 事件	Participants, No. (%) 参与者人数（%）		OR (95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Event 事件	Apixaban ( $n = 204$ ) 阿哌沙班（ $n = 204$ ）	Enoxaparin ( $n = 196$ ) 依诺肝素（ $n = 196$ ）	OR (95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Major bleeding event 严重出血事件	1 (0.5)	1 (0.5)	1.04 (0.07-16.76)	>. 99 >99
Clinically relevant nonmajor bleeding events 临床相关非大出血事件	12 (5.4)	19 (9.7)	1.88 (0.87-4.1)	. 11
Hematoma $^{a}$ 血肿 $^{a}$	1 (0.5)	5 (2.6)	5.31 (0.61-45.9)	. 12
Bruising $^{a}$ 瘀伤 $^{a}$	4 (2.0)	11 (5.6)	2.97 (0.93-9.5)	. 06
Epistaxis 鼻出血	3 (1.5)	2 (1.0)	0.69 (0.11-4.18)	>. 99 >99
Vaginal spotting, discharge, or bleeding 阴道点滴出血、分泌物或出血	4 (2.0)	1 (0.5)	0.26 (0.03-2.3)	. 37
Venous thromboembolism event 静脉血栓栓塞事件	2 (1.0)	3 (1.5)	1.57 (0.26-9.50)	. 68

Table 3. Adverse Events
表 3. 不良事件

Event 事件	Participants, No. (%) 参与者人数（占比）		OR (95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Event 事件	Apixaban ( $n = 204$ ) 阿哌沙班（ $n = 204$ ）	Enoxaparin ( $n = 196$ ) 依诺肝素（ $n = 196$ ）	OR (95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Hospitalized within 28 d after operation 术后 28 天内住院	6 (2.9)	5 (2.6)	0.86 (0.26-2.88)	>. 99 >99
Wound infection 伤口感染	7 (3.4)	10 (5.1)	1.51 (0.56-4.06)	. 41
Dizziness 头晕	10 (4.9)	1 (0.5)	0.10 (0.01-0.79)	. 01
Suspected allergic reaction 疑似过敏反应	1 (0.5)	1 (0.5)	1.04 (0.07-16.76)	>. 99 99
Arthralgia 关节痛	7 (3.4)	2 (1.0)	0.29 (0.06-1.41)	. 18
Skin rash or cellulitis 皮疹或蜂窝组织炎	1 (0.5)	2 (1.0)	2.1 (0.19-23.3)	. 60
Abscess or discharge from incision 脓肿或切口渗液	2 (1.0)	0	NA	. 50
Headache 头痛	7 (3.4)	5 (2.6)	0.74 (0.23-2.3)	. 77

Abbreviation: OR, odds ratio.
缩写：OR，比值比

^{a}

For hematoma and bruising reported, numbers of events were greater than expected.
关于报告的淤血和瘀伤事件，其数量超出预期。

95 % Cl

, 0.01-0.79;

P = .01

). There were no grade 4 or 5 adverse events associated with the study treatment (eTable 2 in Supplement 2).

95 % Cl

, 0.01-0.79;

P = .01

)。与研究治疗相关的 4 级或 5 级不良事件未发生（补充材料 2 中的 eTable 2）。

There were no significant differences in the quality of life SF-8 physical and mental measures in this study, both before and after the intervention, between the 2 groups (median change in physical measures scores, apixaban vs enoxaparin, -5.9 [range, -35.4 to 30.5] vs -6.2 [range, -36.1 to 28.7]; median change in mental measures scores, apixaban vs enoxaparin, 0.8 [range, -30.3 to 30.8 ] vs 0.0 [range, -30.7 to 41.1]). Participant satisfaction was significantly greater in the apixaban group vs the enoxaparin group with regard to ease of taking medication (186 patients [98.9%] vs 110 patients [58.8%]; OR, 0.06; 95% CI, 0.01-0.25;

P < .001

) and pain associated with taking the medication (4 patients [2.1%] vs 92 patients [49.2%]; OR, 9.20; 95% Cl, 2.67-31.82;

P < .001

). Participants did not report a difference in difficulty in remembering to take the medication (149 patients [79.3%] vs 149 patients [79.7%] said it was not difficult to remember) (Table 4). There was no significant difference in adherence between the groups, with 173 participants (84.8%) in the apixaban group and 164 participants (83.7%) in the enoxaparin group missing fewer than 2 days of treatment (OR, 0.92; 95%

Cl, 0.54

1.57; P = .76

). Nearly all participants completed their 28 -day follow-up visit ( 195 patients [95.6%] in the apixaban group vs 190 patients [96.9%] in the enoxaparin group) (Table 4).
本研究中，两组在干预前后的生活质量 SF-8 生理和心理指标均无显著差异（生理指标评分中位数变化：阿哌沙班组 vs 依诺肝素组，-5.9 [范围，-35.4 至 30.5] vs -6.2 [范围，-36.1 至 28.7]；心理指标评分中位数变化：阿哌沙班组 vs 依诺肝素组，0.8 [范围，-30.3 至 30.8] vs 0.0 [范围，-30.7 至 41.1]）。在服药便利性方面（186 例患者[98.9%] vs 110 例患者[58.8%]；OR，0.06；95% CI，0.01-0.25；

P < .001

）及服药相关疼痛方面（4 例患者[2.1%] vs 92 例患者[49.2%]；OR，9.20；95% CI，2.67-31.82；

P < .001

），阿哌沙班组的参与者满意度显著高于依诺肝素组。两组参与者在记忆服药难度方面未报告差异（149 例患者[79.3%] vs 149 例患者[79.7%]表示记忆服药无困难）（表 4）。两组患者的用药依从性无显著差异，阿哌沙班组有 173 名受试者（84.8%）、依诺肝素组有 164 名受试者（83.7%）治疗中断时间少于 2 天（OR 值为 0.92；95%置信区间

Cl, 0.54

至

1.57; P = .76

）。几乎所有受试者都完成了 28 天随访（阿哌沙班组 195 例[95.6%] vs 依诺肝素组 190 例[96.9%]）（见表 4）。

Table 4. Quality of Life, Medication Adherence, and Satisfaction
表 4. 生活质量、用药依从性与满意度

Variable 变量	Apixaban ( $n = 204$ ) 阿哌沙班（ $n = 204$ ）	Enoxaparin ( $n = 196$ ) 依诺肝素（ $n = 196$ ）	Total ( $N = 400$ ) 总计（ $N = 400$ ）	OR(95% CI) 比值比（95%置信区间）	$P$ value $P$ 值
Quality of life (SF-8) score, median (range) 生活质量（SF-8）评分，中位数（范围）
Participants, No. 参与者编号	176	170	346
Physical 物理
Baseline 基线	47.2 (19.5 to 61.8) 47.2（19.5 至 61.8）	47.3 (19.9 to 63.1) 47.3（19.9 至 63.1）	47.2 (19.5 to 63.1) 47.2（19.5 至 63.1）	NA	. 96
End of study 研究结束	39.2 (21.0 to 58.6) 39.2（21.0 至 58.6）	38.5 (17.8 to 60.7) 38.5（17.8 至 60.7）	39.0 (17.8 to 60.7) 39.0（17.8 至 60.7）	NA	. 76
Change 改变	-5.9 (-35.4 to 30.5) -5.9 (-35.4 至 30.5)	-6.2 (-36.1 to 28.7) -6.2 (-36.1 至 28.7)	-6.0 (-36.1 to 30.5) -6.0 (-36.1 至 30.5)	NA	. 75
Mental 心理
Baseline 基线	50.7 (19.2 to 64.5) 50.7（19.2 至 64.5）	49.7 (16.2 to 62.7) 49.7（16.2 至 62.7）	50.1 (16.2 to 64.5) 50.1（16.2 至 64.5）	NA	. 64
End of study 研究结束	50.7 (18.5 to 69.4) 50.7（18.5 至 69.4）	49.3 (19.7 to 62.2) 49.3（19.7 至 62.2）	49.8 (18.5 to 69.4) 49.8（18.5 至 69.4）	NA	. 35
Change 改变	0.8 (-30.3 to 30.8) 0.8 (-30.3 至 30.8)	0.0 (-30.7 to 41.1) 0.0 (-30.7 至 41.1)	0.0 (-30.7 to 41.1) 0.0 (-30.7 至 41.1)	NA	. 52
Satisfaction survey, participants, No. (%) $^{a}$ 满意度调查，参与者人数（%） $^{a}$
Participants, No. 参与者人数	188	187	375
Difficulty remembering to take medication? 是否难以记住服药？
Agree 同意	23 (12.2)	23 (12.3)	46 (12.3)	1.07 (0.43-2.65)	. 99
Neutral 中立	16 (8.5)	15 (8.0)	31 (8.3)	1 [Reference] 1 [参考文献]
Disagree 不同意	149 (79.3)	149 (79.7)	298 (79.5)	1.07 (0.51-2.24)
Pain associated with taking medication? 服药时伴随疼痛？
Agree 同意	4 (2.1) $^{a}$	92 (49.2)	96 (25.7)	9.20 (2.67-31.82)	<. 001
Neutral 中立	10 (5.3)	25 (13.4)	35 (9.4)	1 [Reference] 1 [参考文献]
Disagree 不同意	173 (92.5)	70 (37.4)	243 (65.0)	0.16 (0.07-0.36)
Was medication easy to take? 服药是否方便？
Agree 同意	186 (98.9)	110 (58.8)	296 (78.9)	0.06 (0.01-0.25)	<. 001
Neutral 中立	2 (1.1)	21 (11.2)	23 (6.1)	1 [Reference] 1 [参考文献]
Disagree 不同意	0	56 (29.9)	56 (14.9)	NA $^{b}$ 不适用 $^{b}$
Adherent (missed <2 d) 依从（漏服<2 天）	173 (84.8)	164 (83.7)	337 (84.3)	0.92 (0.54-1.57)	. 76
Completed study visit 完成研究访视
28 d 28 天	195 (95.6)	190 (96.9)	385 (96.3)	0.98 (0.14-6.99)	>. 99 >99
90 d 90 天	168 (82.4)	163 (83.2)	331 (82.8)	1.46 (0.24-8.82)	>. 99 >99

| Variable | Apixaban ( $\mathrm{n}=204$ ) | Enoxaparin ( $\mathrm{n}=196$ ) | Total ( $\mathrm{N}=400$ ) | OR(95% CI) | $P$ value | | :--- | :--- | :--- | :--- | :--- | :--- | | Quality of life (SF-8) score, median (range) | | | | | | | Participants, No. | 176 | 170 | 346 | | | | Physical | | | | | | | Baseline | 47.2 (19.5 to 61.8) | 47.3 (19.9 to 63.1) | 47.2 (19.5 to 63.1) | NA | . 96 | | End of study | 39.2 (21.0 to 58.6) | 38.5 (17.8 to 60.7) | 39.0 (17.8 to 60.7) | NA | . 76 | | Change | -5.9 (-35.4 to 30.5) | -6.2 (-36.1 to 28.7) | -6.0 (-36.1 to 30.5) | NA | . 75 | | Mental | | | | | | | Baseline | 50.7 (19.2 to 64.5) | 49.7 (16.2 to 62.7) | 50.1 (16.2 to 64.5) | NA | . 64 | | End of study | 50.7 (18.5 to 69.4) | 49.3 (19.7 to 62.2) | 49.8 (18.5 to 69.4) | NA | . 35 | | Change | 0.8 (-30.3 to 30.8) | 0.0 (-30.7 to 41.1) | 0.0 (-30.7 to 41.1) | NA | . 52 | | Satisfaction survey, participants, No. (%) ${ }^{\text {a }}$ | | | | | | | Participants, No. | 188 | 187 | 375 | | | | Difficulty remembering to take medication? | | | | | | | Agree | 23 (12.2) | 23 (12.3) | 46 (12.3) | 1.07 (0.43-2.65) | . 99 | | Neutral | 16 (8.5) | 15 (8.0) | 31 (8.3) | 1 [Reference] | | | Disagree | 149 (79.3) | 149 (79.7) | 298 (79.5) | 1.07 (0.51-2.24) | | | Pain associated with taking medication? | | | | | | | Agree | 4 (2.1) ${ }^{\text {a }}$ | 92 (49.2) | 96 (25.7) | 9.20 (2.67-31.82) | <. 001 | | Neutral | 10 (5.3) | 25 (13.4) | 35 (9.4) | 1 [Reference] | | | Disagree | 173 (92.5) | 70 (37.4) | 243 (65.0) | 0.16 (0.07-0.36) | | | Was medication easy to take? | | | | | | | Agree | 186 (98.9) | 110 (58.8) | 296 (78.9) | 0.06 (0.01-0.25) | <. 001 | | Neutral | 2 (1.1) | 21 (11.2) | 23 (6.1) | 1 [Reference] | | | Disagree | 0 | 56 (29.9) | 56 (14.9) | NA ${ }^{\text {b }}$ | | | Adherent (missed <2 d) | 173 (84.8) | 164 (83.7) | 337 (84.3) | 0.92 (0.54-1.57) | . 76 | | Completed study visit | | | | | | | 28 d | 195 (95.6) | 190 (96.9) | 385 (96.3) | 0.98 (0.14-6.99) | >. 99 | | 90 d | 168 (82.4) | 163 (83.2) | 331 (82.8) | 1.46 (0.24-8.82) | >. 99 |

Discussion 讨论

Oral apixaban is a potentially safe alternative with regard to bleeding compared with subcutaneous enoxaparin in women undergoing surgery for gynecologic cancer. There was no significant difference in major or CRNM bleeding events between the 2 groups of this randomized clinical trial. Adherence rates and adverse events between both modalities appeared to be similar, with significantly greater satisfaction outcomes in participants taking apixaban. Although this study was underpowered for the prevention of VTE, rates were slightly lower in the apixaban group, although the difference was not significant. This finding suggests that this modality is effective in preventing VTE with a greater sample size of high-risk women with gynecologic cancer. Since this study started, a retrospective study

^{28}

has reported lower VTE rates associated with minimally invasive surgeries. In addition, to our knowledge, this study represents the first prospective trial in which an oral factor Xa inhibitor, apixaban, was safely used in patients undergoing laparotomy. Given the number of cancer operations that require large abdominal incisions in a variety of disease sites (eg, pancreas or colon), these data could be considered in other disease sites that require extensive abdominal debulking.
与皮下注射依诺肝素相比，口服阿哌沙班对接受妇科癌症手术的女性而言可能是更安全的出血风险替代方案。这项随机临床试验显示两组在主要出血或临床相关非大出血事件方面无显著差异。两种给药方式的用药依从性和不良事件发生率相似，但阿哌沙班组患者的满意度显著更高。虽然本研究在预防静脉血栓栓塞（VTE）方面统计效力不足，但阿哌沙班组的 VTE 发生率略低（差异无统计学意义）。该发现表明，若扩大高危妇科癌症患者样本量，这种给药方式能有效预防 VTE。自本研究启动以来，一项回顾性研究

^{28}

报告微创手术相关的 VTE 发生率更低。此外据我们所知，本研究是首个前瞻性证实口服 Xa 因子抑制剂阿哌沙班可安全用于开腹手术患者的临床试验。鉴于许多癌症手术（如胰腺或结肠手术）需要在腹部进行大面积切口，这些数据也可供其他需要广泛腹部减瘤手术的疾病参考。

Previous studies

^{5}

have shown the need for anticoagulation in women undergoing surgical debulking of gynecologic cancers. Current recommendations to decrease the risk of VTE have included subcutaneous enoxaparin for 28 days but they have been met with adherence issues because of pain and bruising at injection site and cost.

^{29}

Given the potential lethality of VTE in this patient population, effective and convenient prophylaxis is critical in reducing this burden. Our findings suggest that the risk of VTE is still a concern even with appropriate use of anticoagulation drugs and should be considered for the full 28 days after surgery.
先前研究

^{5}

表明，妇科癌症减瘤手术患者需接受抗凝治疗。目前降低静脉血栓栓塞（VTE）风险的建议包括持续 28 天的依诺肝素皮下注射，但因注射部位疼痛淤青及费用问题存在依从性难题。

^{29}

考虑到 VTE 对该患者群体的致命威胁，便捷有效的预防措施对减轻这一负担至关重要。我们的研究结果表明，即使规范使用抗凝药物，VTE 风险仍不容忽视，术后 28 天内都应持续关注。

Strengths and Limitations
优势与局限性

This study has several strengths. First, randomization allowed for potential biases to be substantially reduced and allowed for appropriate balance between the 2 interventions. Both groups had patients with equal numbers disease sites, comorbidities, true cancer diagnoses, and median body mass index. Participants also underwent a variety of surgical procedures, thus increasing the broad applicability of the data. Satisfaction was substantially higher in the apixaban group, with patients stating ease of use as a major factor in adherence.
本研究具有多项优势。首先，随机化设计大幅降低了潜在偏倚，确保两种干预措施之间的平衡性。两组患者在病灶数量、合并症、确诊癌症比例及中位体重指数方面均保持均衡。受试者还接受了多种外科手术，从而增强了数据的广泛适用性。阿哌沙班组患者满意度显著更高，用药便捷性被报告为坚持治疗的主要因素。

Notably, the

83.7 %

rate of adherence to injectables in this study was higher than the rate of

60 %

reported in prior observational studies

^{14}

of patients undergoing orthopedic surgery. In this study, the apixaban adherence rate was

84.8 %

. Participation in a clinical trial itself may increase the likelihood of adherence. In addition, patients in this study were followed up for 2 weeks postoperatively in person vs by phone and may have been more motivated by serious illness to adhere to medications. We hypothesize that the compliance rates in the real-world setting would reflect the satisfaction we found with taking the medication and that patients taking an oral medication may have higher real-world compliance rates compared with the known real-world compliance rates for those taking enoxaparin daily for a short period.
值得注意的是，本研究中对注射剂的

83.7 %

依从率高于既往骨科手术患者观察性研究中报告的

60 %

依从率

^{14}

。本研究中阿哌沙班的依从率为

84.8 %

。参与临床试验本身可能会提高用药依从性。此外，本研究患者术后通过面对面（而非电话）随访两周，重症患者可能更有动力坚持用药。我们推测真实世界中的依从率会反映患者对服药体验的满意度，且口服药物患者的真实世界依从率可能高于已知的短期每日使用依诺肝素患者的真实依从率。

Limitations of this study include lower than expected rates of VTE and bleeding in the study population, which may be associated with the magnitude of the effect of the primary outcome. Alternatively, the lower than expected VTE rate may be attributed to the high compliance rate in this controlled environment, and it may be difficult to represent the real-world VTE rate. In addition, this study was designed to evaluate the safety outcome of bleeding, and although the data suggest that apixaban is effective, a true randomized noninferiority trial would have to be executed to confirm these findings. This study was also limited in that we could not effectively blind the patients to the study drug without compromising the minimal and justified risk to the patient because of the 2 drastically different study drug administration methods.
本研究的局限性包括研究人群中静脉血栓栓塞（VTE）和出血事件发生率低于预期，这可能与主要结局效应量相关。另一种可能是，VTE 发生率低于预期可归因于受控环境中的高依从性，因此可能难以反映真实世界的 VTE 发生率。此外，本研究旨在评估出血这一安全性结局，虽然数据表明阿哌沙班具有疗效，但仍需开展真正的随机非劣效性试验来验证这些发现。本研究还存在另一局限：由于两种研究药物给药方式存在显著差异，若要在不损害患者最小合理风险的前提下对患者实施有效盲法存在困难。

Conclusions 结论

These findings suggest that oral apixaban is a safe potential alternative to subcutaneous enoxaparin for thromboprophylaxis in women undergoing surgery for gynecologic cancer. Satisfaction measures were markedly better in the apixaban group, and adherence rates were similar between both modalities in the controlled environment of this trial. Surgeons should continue to use appropriate postoperative VTE prophylaxis in high-risk surgical oncology patients to help prevent this potentially life-threatening outcome and may consider at their discretion the safety of thromboprophylaxis options.
这些研究结果表明，对于接受妇科癌症手术的女性患者而言，口服阿哌沙班可作为皮下注射依诺肝素的一种安全替代方案用于血栓预防。在本试验的受控环境中，阿哌沙班组的满意度指标显著更优，且两种给药方式的依从性相当。外科医生应继续对高风险肿瘤手术患者采取适当的术后静脉血栓栓塞预防措施，以帮助预防这种可能危及生命的并发症，并可根据具体情况考虑不同血栓预防方案的安全性。

ARTICLE INFORMATION 文章信息

Accepted for Publication: April 3, 2020.
收稿日期：2020 年 4 月 3 日
Published: June 26, 2020. doi:10.1001/jamanetworkopen.2020.7410
出版日期：2020 年 6 月 26 日 doi:10.1001/jamanetworkopen.2020.7410
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020
开放获取：本文依据 CC-BY-NC-ND 许可协议开放获取。© 2020
Guntupalli SR et al. JAMA Network Open.
Guntupalli SR 等. 《美国医学会杂志网络开放》
Corresponding Author: Saketh R. Guntupalli, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine at Denver, 12631 E 17th Ave, PO Box 4491, Aurora, CO 80045 (saketh.guntupalli@cuanschutz.edu).
通讯作者：Saketh R. Guntupalli 医学博士，丹佛科罗拉多大学医学院妇产科系妇科肿瘤科，地址：科罗拉多州奥罗拉市东 17 大道 12631 号 4491 信箱，邮编 80045（电子邮箱：saketh.guntupalli@cuanschutz.edu）。

Author Affiliations: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine at Denver, Aurora (Guntupalli, Brennecke, Behbakht, Tayebnejad, Breed, Babayan, Cheng, Ramzan, Wheeler, Corr, Lefkowits, Flink); Division of Family Planning, Department of Obstetrics and Gynecology, University of Colorado School of Medicine at Denver, Aurora (Sheeder); Keck School of Medicine, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles (Matsuo).
作者单位：丹佛科罗拉多大学医学院妇产科系妇科肿瘤科，奥罗拉（Guntupalli、Brennecke、Behbakht、Tayebnejad、Breed、Babayan、Cheng、Ramzan、Wheeler、Corr、Lefkowits、Flink）；丹佛科罗拉多大学医学院妇产科系计划生育科，奥罗拉（Sheeder）；南加州大学凯克医学院妇产科系妇科肿瘤科，洛杉矶（Matsuo）。
Author Contributions: Drs Guntupalli and Flink had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
作者贡献：Guntupalli 博士和 Flink 博士能够完全获取研究中的所有数据，并对数据的完整性和数据分析的准确性负责。

Concept and design: Guntupalli, Behbakht, Cheng, Sheeder, Flink.
概念与设计：Guntupalli、Behbakht、Cheng、Sheeder、Flink
Acquisition, analysis, or interpretation of data: Guntupalli, Brennecke, Tayebnejad, Breed, Babayan, Cheng, Ramzan, Wheeler, Corr, Lefkowits, Sheeder, Matsuo, Flink.
数据采集、分析或解释：Guntupalli、Brennecke、Tayebnejad、Breed、Babayan、Cheng、Ramzan、Wheeler、Corr、Lefkowits、Sheeder、Matsuo、Flink

Drafting of the manuscript: Guntupalli, Behbakht, Sheeder, Flink.
稿件起草：Guntupalli、Behbakht、Sheeder、Flink。
Critical revision of the manuscript for important intellectual content: Guntupalli, Brennecke, Tayebnejad, Breed, Babayan, Cheng, Ramzan, Wheeler, Corr, Lefkowits, Sheeder, Matsuo, Flink.
对文稿重要学术内容进行批判性修订的人员：Guntupalli、Brennecke、Tayebnejad、Breed、Babayan、Cheng、Ramzan、Wheeler、Corr、Lefkowits、Sheeder、Matsuo、Flink。

Statistical analysis: Guntupalli, Brennecke, Babayan, Sheeder, Flink.
统计分析：Guntupalli、Brennecke、Babayan、Sheeder、Flink。
Obtained funding: Guntupalli, Flink.
资金获取：Guntupalli、Flink。
Administrative, technical, or material support: Guntupalli, Behbakht, Breed, Cheng, Wheeler, Corr, Sheeder, Matsuo.
提供行政、技术或材料支持人员：Guntupalli、Behbakht、Breed、Cheng、Wheeler、Corr、Sheeder、Matsuo。

Supervision: Guntupalli, Cheng, Corr, Lefkowits, Sheeder, Flink.
项目监督：Guntupalli、Cheng、Corr、Lefkowits、Sheeder、Flink。
Conflict of Interest Disclosures: Dr Matsuo reported receiving an honorarium other from Chugai, editorial expenses from Springer, and investigator meeting attendance expenses from VBL Therapeutics outside the submitted work. Dr Flink reported receiving a Bristol-Myers Squibb Investigator Initiated award during the conduct of the study. No other disclosures were reported.
利益冲突声明：Matsuo 博士报告在提交工作之外收取了中外制药的酬金、Springer 的编辑费用以及 VBL Therapeutics 的研究者会议出席费用。Flink 博士报告在研究期间获得了百时美施贵宝研究者发起奖项。其他作者均无利益冲突声明。

Funding/Support: This study was an independent, investigator-initiated trial supported by Bristol-Myers-Squibb and Pfizer, Inc.
资金支持：本研究是由百时美施贵宝和辉瑞公司支持的独立研究者发起试验。

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
资助方/主办方角色：资助方未参与研究设计与实施；数据收集、管理、分析与解释；文稿撰写、审阅或批准；以及决定提交论文发表。

Meeting Presentation: This article was presented at the 17th Biennial Meeting of the International Gynecologic Cancer Society; September 19, 2019; Rio de Janeiro, Brazil.
会议报告：本文曾在 2019 年 9 月 19 日于巴西里约热内卢举行的第 17 届国际妇科肿瘤学会双年会上进行展示。

Data Sharing Statement: See Supplement 3.
数据共享声明：见补充材料 3。
Additional Contributions: Amanda Glickman, MD (Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine at Denver), provided editing assistance; she was compensated for her time. The research pharmacy at University of Colorado Hospital distributed study
其他贡献者：丹佛科罗拉多大学医学院妇产科妇科肿瘤分部的 Amanda Glickman 医学博士提供了编辑协助，其工作时间已获得相应报酬。科罗拉多大学医院的研究药房负责研究
medication. Marissa Aldana, CCRP, BS (Keck School of Medicine, Department of Obstetrics and Gynecology, University of Southern California), contributed to data collection; she was not compensated beyond her regular salary. We are grateful to the patients who took the time to participate in this study.
药物分发。南加州大学凯克医学院妇产科的 Marissa Aldana（CCRP 认证，理学学士）参与了数据收集工作，除常规薪资外未获得额外报酬。我们衷心感谢所有抽空参与本研究的患者。

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SUPPLEMENT 1. 附录 1.
Trial Protocol 试验方案

SUPPLEMENT 2. 附录 2.
eTable 1. Description of Major Bleeding and Venous Thromboembolic Events
e 表 1. 主要出血事件与静脉血栓栓塞事件说明
eTable 2. Grade Level of Related and Anticipated Adverse Events
电子表格 2. 相关及预期不良事件分级表
eFigure. Treatment Diagram
e 图. 治疗流程图

SUPPLEMENT 3. 补充材料 3.
Data Sharing Statement 数据共享声明

Abbreviations: NA, not applicable; OR, odds ratio.
缩写：NA，不适用；OR，比值比。
$^{b}$ Odds ratios and $95 %$ CIs cannot be calculated for values of 0 .
$^{b}$ 当数值为 0 时，无法计算比值比和 $95 %$ 置信区间。
$^{a}$ One patient missed this question.
$^{a}$ 有一名患者未回答此问题。