加拿大渥太华大学Marc Carrier团队研究了低分子肝素延长围手术期血栓预防治疗对结直肠癌术后无病生存期的疗效和安全性。相关论文于2022年9月13日发表在《英国医学杂志》上。

为了确定低分子肝素延长围手术期血栓预防的有效性和安全性，以评估结直肠癌切除患者的无病生存期，2011年10月25日至2020年12月31日，研究组在加拿大魁北克省和安大略省的12家医院进行了一项多中心、开放标签、随机对照试验。共招募了614名患者，年龄≥18岁，符合病理证实的结肠或直肠侵袭性腺癌，无转移性疾病证据，血红蛋白浓度≥8g/dL，并计划进行手术切除。

将患者随机分组，分别接受每日4500 IU皮下注射亭扎肝素进行延长时间血栓预防，从决定手术开始至术后持续56天，或仅接受住院术后血栓预防。主要结局是三年无疾病生存期，定义为无局部复发、远处转移、第二原发（同一癌症）、第二原发（其他癌症）或死亡的生存期。次要结局包括静脉血栓栓塞、术后重大出血并发症和5年总生存率。对意向治疗人群进行分析。

试验在中期分析无效后过早停止招募。延长治疗时间组中有235名患者（77%）发生主要结局，住院血栓预防组中有243名（79%），风险比为1.1，组间差异不显著。延长治疗时间组术后有5例（2%）患者发生静脉血栓栓塞，住院血栓预防组中有4例（1%）。术后第一周，延长治疗时间组中有1人（<1%）发生与手术相关的大出血，住院血栓预防组中有6人（2%）报告了大出血。延长治疗时间组中有272例（89%）患者5年后仍存活，住院血栓预防组中有280例（91%），两组5年总生存率无显著差异，危险比为1.12。

研究结果表明，与仅住院术后血栓预防相比，延长使用亭扎肝素的围手术期抗凝时间并不能改善接受手术切除的结直肠癌患者的无病生存期或总体生存期。静脉血栓栓塞和术后大出血的发生率较低，两组间相似。

附：英文原文

Title: Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

Author: Rebecca C Auer, Michael Ott, Paul Karanicolas, Muriel Rebecca Brackstone, Shady Ashamalla, Joel Weaver, Vicky Tagalakis, Marylise Boutros, Peter Stotland, Antonio Caycedo Marulanda, Husein Moloo, Shiva Jayaraman, Suni Patel, Grégoire Le Gal, Silvana Spadafora, Steven MacLellan, Daniel Trottier, Derek Jonker, Timothy Asmis, Ranjeeta Mallick, Amanda Pecarskie, Tim Ramsay, Marc Carrier

Issue&Volume: 2022/09/13

Abstract:

Objective To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer.

Design Multicentre, open label, randomised controlled trial.

Settings 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020.

Participants 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection.

Interventions Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only.

Main outcome measures Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population.

Results The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1).

Conclusions Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups.

DOI: 10.1136/bmj-2022-071375

Source: https://www.bmj.com/content/378/bmj-2022-071375