美国华盛顿大学医学系Brian F. Gage研究组近日比较了低强度与标准强度华法林预防髋关节或膝关节置换术患者静脉血栓栓塞（VTE）或死亡的影响。2019年9月3日出版的《美国医学会杂志》发表了这一成果。

2011年4月至2016年10月，随机遗传信息学试验（GIFT）在美国的6个医疗中心招募了1650名65岁及以上的参与者，平均年龄为72.1岁，63.6%为女性，91.0%为白人。这些患者均选择性行髋关节或膝关节置换术，且使用华法林预防深静脉血栓形成。823名被随机分配至国际标准化比值（INR）目标为1.8组（低强度组），827名被随机分配至INR目标为2.5组（标准强度组）。

1597名（96.8%）参与者至少接受1剂华法林并纳入初步分析。低强度组发生VTE和死亡的比率为5.1%，标准强度组为3.8%，差异为1.3%；低强度组中0.4%的患者出现严重出血，标准强度组为0.9%，差异为−0.5%；低强度组中4.5%的患者INR值≥4，标准强度组为12.2%，差异为-7.8%。

综上，在接受髋关节或膝关节置换术并接受华法林预防治疗的老年患者中，INR目标1.8与2.5相比VTE或死亡的综合风险反而升高。然而，该试验样本有限，仍需进一步研究。

附：英文原文

Title: Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty  A Randomized Clinical Trial

Author: Brian F. Gage, MD, MSc1; Anne R. Bass, MD2; Hannah Lin, BA1,3; Scott C. Woller, MD4,5; Scott M. Stevens, MD4,5; Noor Al-Hammadi, MBChB, MPH1; Jeffrey L. Anderson, MD5,6; Juan Li, MPH1; Tomás Rodriguez Jr, MS1; J. Philip Miller, AB1; Gwendolyn A. McMillin, PhD7; Robert C. Pendleton, MD5; Amir K. Jaffer, MD, MBA8; Cristi R. King, BS1; Brandi Whipple, BS1; Rhonda Porche-Sorbet, MS1; Lynnae Napoli, BS5; Kerri Merritt, BA2; Anna M. Thompson, BA1,9; Gina Hyun, MD1,10; Wesley Hollomon, MD, MBA11; Robert L. Barrack, MD12; Ryan M. Nunley, MD12; Gerard Moskowitz, PhD1; Victor Dávila-Román, MD1; Charles S. Eby, MD1,13

Issue&Volume: Vol 322 No 9

Abstract：

Importance  The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown.

Objective  To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery.

Design, Setting, and Participants  The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.

Interventions  In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application.

Main Outcomes and Measures  The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more.

Results  Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, −∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of −0.5% (95% CI, −1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of −7.8% (95% CI, −10.5% to −5.1%).

Conclusions and Relevance  Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted.