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Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists—The PROPER3 Randomized Clinical Trial
Annals of Emergency Medicine ( IF 6.2 ) Pub Date : 2021-09-15 , DOI: 10.1016/j.annemergmed.2021.06.016
Rahat A Abdoellakhan 1 , Nakisa Khorsand 2 , Ewoud Ter Avest 3 , Heleen Lameijer 4 , Laura M Faber 5 , Paula F Ypma 6 , Laurens Nieuwenhuizen 7 , Nic J G M Veeger 8 , Karina Meijer 1
Affiliation  

Study objective

To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation.

Methods

In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than −6%. When estimating sample size, we assumed that fixed dosing would be 4% superior.

Results

From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval −13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0).

Conclusion

The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.



中文翻译:

凝血酶原复合物浓缩物的固定剂量与可变剂量治疗维生素 K 拮抗剂的出血并发症——PROPER3 随机临床试验

学习目标

确定 1000 IU 4 因子凝血酶原复合物浓缩物 (4F-PCC) 的固定剂量是否与基于体重和国际标准化比率 (INR) 的传统可变剂量逆转维生素 K 拮抗剂 (VKA) 抗凝作用一样有效。

方法

在这项开放标签、多中心、随机临床试验中,需要用 4F-PCC 逆转 VKA 的非颅内出血患者被分配到 1,000-IU 固定剂量的 4F-PCC 或可变剂量。主要结果是根据国际血栓形成和止血学会定义的有效止血患者的比例。该设计是非劣效性的,95% 置信区间不超过 -6%。在估计样本量时,我们假设固定剂量会好 4%。

结果

从 2015 年 10 月到 2020 年 1 月,由于入组率下降,310 名预期患者中有 199 名在研究终止前被纳入。在 199 名患者中,159 名患者被允许进行符合方案分析。固定剂量组的有效止血率为 87.3%(n=69 of 79),而可变剂量组为 89.9%(n=71 of 79)(风险差异 2.5%,95% 置信区间 -13.3 至 7.9%,P = .27)。固定剂量的中位门到针时间为 109 分钟(范围 16 至 796),可变剂量为 142 分钟(17 至 1076)(P =.027)。4F-PCC 输注后 60 分钟 INR 低于 2.0 的比例分别为 91.2% 和 91.7%(P = 1.0)。

结论

绝大多数患者在使用 4F-PCC 后临床结果良好;然而,无法证明固定剂量的非劣效性,因为设计假设固定剂量将优于 4%。固定剂量缩短了从门到针的时间,两种给药方案的 INR 降低相似。

更新日期:2021-09-15
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