俄罗斯莫斯科国立谢东诺夫第一医科大学Sam Schulman团队联合美国约翰霍普金斯儿童中心Neil A. Goldenberg团队比较了抗凝治疗6周与3个月对21岁以下诱发静脉血栓栓塞患者复发和出血事件的影响。这一研究成果于2022年1月11日发表在《美国医学会杂志》上。

在小于21岁的患者中，静脉血栓栓塞的最佳抗凝治疗持续时间是未知的。

为了验证对21岁以下的患者进行6周的抗凝治疗是否优于3个月的常规治疗，2008-2021年，研究组在5个国家的42个中心进行了一项随机临床试验，共招募417名年龄小于21岁的急性诱发静脉血栓栓塞患者。主要排除严重抗凝缺陷或此前曾患静脉血栓栓塞的患者。对无持续性抗磷脂抗体，且在诊断后6周重复影像学检查血栓消除或未完全闭塞的患者进行随机分组。于2021年1月完成对主要结局的最终随访。

将符合标准的诱发静脉血栓栓塞患者随机分组，其中207名接受为期6周的抗凝治疗，210名接受为期3个月的抗凝治疗。主要疗效和安全性结局为治疗组盲测的中央判定1年内症状性复发静脉血栓栓塞和临床相关出血事件。主要分析是按方案人群的非劣效性。非劣效性边缘包含双变量权衡，包括症状性复发静脉血栓栓塞的绝对值增加0%，与临床相关出血事件的绝对风险降低4%。

在417名随机分组的患者中，297名符合按方案分析的主要人群标准，中位年龄为8.3岁，49%为女性。6周抗凝治疗组中主要疗效结局K-M估计1年累积发病率为0.66%，3个月抗凝治疗组为0.7%；主要安全结局的发生率分别为0.65%和0.7%。两组间复发静脉血栓栓塞和临床相关出血事件的绝对风险差异证明了非劣效性。6周抗凝治疗组和3个月抗凝治疗组的不良事件发生率分别为26%和32%；最常见的不良事件是发热，分别为1.9%和3.4%。

研究结果表明，在年龄小于21岁的诱发静脉血栓栓塞患者中，抗凝治疗6周与治疗3个月相比，符合基于复发静脉血栓栓塞风险与出血风险权衡的非劣效性标准。

附：英文原文

Title: Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial

Author: Neil A. Goldenberg, John M. Kittelson, Thomas C. Abshire, Marc Bonaca, James F. Casella, Rita A. Dale, Jonathan L. Halperin, Frances Hamblin, Craig M. Kessler, Marilyn J. Manco-Johnson, Robert F. Sidonio, Alex C. Spyropoulos, P. Gabriel Steg, Alexander G. G. Turpie, Sam Schulman, Kids-DOTT Trial Investigators and the ATLAS Group, James A French, John H Fargo, Shelley E Crary, Riten Kumar, Rachel F Grace, Cameron C Trenor, Hope P Wilson, Lee M Hilliard, Gary M Woods, Kavita Patel, Neil A Goldenberg, Eric J Lowe, Julie A Jaffray, Guy A Young, Madhvi A Rajpurkar, Jennifer G Davila, Arash Mahajerin, James Cooper, Sriya W Gunawardena, Ayesha N Zia, Janna M Journeycake, Shannon L Carpenter, Michael M Guerrera, Yaser A Diab, Cristina C Tarango, Ralph A Gruppo, Suchitra S Acharya, Marcella D Torres, Linda G Shaffer, Robert C Mignacca, Kristina M Haley, Michael Recht, Courtney D Thornburg, Nirmish R Shah, Craig A Mullen, Deanna S Mitchell, Charles Nakar, Marisol Betensky, Courtney E Lawrence, Clifford M Takemoto, Clara Lo, Ajovi B Scott-Emuakpor, Roshni Kulkarni, Alexandra J Borst, Sarah H OBrien, Fernando F Corales-Medina, Shalu Narang, Nicole E Kucine, Michael Wang, Arun R Panigrahi, Kerry K McGowan, Stuart L Cramer, Smita C Dandekar, Frederico Xavier, Kristina M Knoll, Anupam R Verma, Amy E Geddes

Issue&Volume: 2022/01/11

Abstract:

Importance  Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown.

Objective  To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age.

Design, Setting, and Participants  Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021.

Interventions  Total duration for anticoagulant therapy of 6 weeks (n=207) vs 3 months (n=210) for provoked venous thromboembolism.

Main Outcomes and Measures  The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve).

Results  Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively).

Conclusions and Relevance  Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk.

DOI: 10.1001/jama.2021.23182

Source: https://jamanetwork.com/journals/jama/article-abstract/2787908