Department of Medicine, Washington University in St Louis, St Louis, Missouri.
Department of Medicine, Hospital for Special Surgery, New York, New York.
JAMA. 2019 Sep 3;322(9):834-842. doi: 10.1001/jama.2019.12085.
The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown.
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.
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.
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.
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%).
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.
ClinicalTrials.gov Identifier: NCT01006733.
最近接受过关节置换术的华法林治疗患者，预防静脉血栓栓塞（VTE）的最佳国际标准化比值（INR）尚不清楚。
确定在骨科手术后，INR 目标值为 1.8 与 2.5 相比，用于 VTE 预防的安全性和有效性。
设计、地点和参与者：在 6 家美国医疗中心，有 1650 名年龄在 65 岁或以上的患者接受华法林治疗，用于择期髋关节或膝关节置换术，进行了这项随机遗传信息试验（GIFT）的华法林预防深静脉血栓形成。招募于 2011 年 4 月开始，随访于 2016 年 10 月结束。
在 2×2 析因设计中，参与者被随机分配到 INR 目标值为 1.8（n=823）或 2.5（n=827），以及基因指导或临床指导的华法林剂量。在治疗的前 11 天，开放标签华法林剂量由一个网络应用程序指导。
主要结局是 VTE（60 天内）或死亡（30 天内）的复合结局。参与者术后接受了筛查性双功超声检查。假设 INR 目标值为 1.8 与 INR 目标值为 2.5 相比，VTE 的绝对风险的非劣效性边际为 3%。次要终点是出血和 INR 值为 4 或更高。
在 1650 名随机分配的患者（平均年龄 72.1 岁；1049 名女性[63.6%]；1502 名白人[91.0%]）中，1597 名（96.8%）至少接受了 1 剂华法林，并纳入了主要分析。低强度华法林组（INR 目标值为 1.8）的主要复合结局（VTE 或死亡）发生率为 5.1%（41/804），而标准治疗华法林组（INR 目标值为 2.5）为 3.8%（30/793），差异为 1.3%（单侧 95%置信区间，-∞至 3.05%，P=0.06 表示非劣效性）。低强度组 0.4%的患者发生大出血，标准强度组 0.9%的患者发生大出血，差异为-0.5%（95%置信区间，-1.6%至 0.4%）。低强度组 4.5%的患者 INR 值为 4 或更高，标准强度组 12.2%的患者 INR 值为 4 或更高，差异为-7.8%（95%置信区间，-10.5%至-5.1%）。
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，与 2.5 相比，INR 目标值为 1.8 并未达到 VTE 或死亡复合结局风险的非劣效性标准。然而，该试验可能没有足够的能力达到这一标准，可能需要进一步的研究。
ClinicalTrials.gov 标识符：NCT01006733。
