4 因子凝血酶原复合物在接受维生素 K 拮抗剂治疗的大出血患者中的疗效和安全性：一项随机、血浆对照、IIIb 期研究。
Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.
机构信息
University of Texas Southwestern Medical Center, Dallas (R.S.); Seton/University of Texas Southwestern Clinical Research Institute of Austin, Dell Children's Medical Center, University Medical Center at Brackenridge, Austin, TX (T.J.M.); University of Rochester Medical Center, Rochester, NY (M.A.R.); CSL Behring LLC, King of Prussia, PA (A.M., B.L.D.); CSL Behring GmbH, Marburg, Germany (A.S.); and Massachusetts General Hospital, Boston (J.N.G.).
出版信息
Circulation. 2013 Sep 10;128(11):1234-43. doi: 10.1161/CIRCULATIONAHA.113.002283. Epub 2013 Aug 9.
BACKGROUND
Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal.
METHODS AND RESULTS
In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event.
CONCLUSIONS
4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels.
CLINICAL TRIAL REGISTRATION URL
http://www.clinicaltrials.gov. Unique identifier: NCT00708435.
背景
正在服用维生素 K 拮抗剂的患者发生大出血时需要快速逆转维生素 K 拮抗剂。我们进行了一项前瞻性临床试验，比较了非活化的 4 因子凝血酶原复合物浓缩物（4F-PCC）与血浆在紧急逆转维生素 K 拮抗剂中的作用。
方法和结果
在这项 IIIb 期、多中心、开放性、非劣效性试验中，非手术患者被随机分配至 4F-PCC（含有凝血因子 II、VII、IX 和 X 以及蛋白 C 和 S）或血浆组。主要分析检测了 4F-PCC 在输注开始后 24 小时止血效果和输注结束后 0.5 小时国际标准化比值（INR）校正（≤1.3）的两个主要复合终点方面是否不劣于血浆。意向治疗疗效人群包括 202 例患者（4F-PCC 组 98 例，血浆组 104 例）。4F-PCC 组的中位（范围）基线 INR 为 3.90（1.8-20.0），血浆组为 3.60（1.9-38.9）。72.4%接受 4F-PCC 治疗的患者达到有效止血，65.4%接受血浆治疗的患者达到有效止血，表明 4F-PCC 不劣效（差异 7.1%[95%置信区间：-5.8 至 19.9]）。62.2%接受 4F-PCC 治疗的患者快速降低 INR，9.6%接受血浆治疗的患者降低 INR，表明 4F-PCC 具有优势（差异 52.6%[95%置信区间：39.4 至 65.9]）。输注开始后 0.5 至 3 小时，4F-PCC 组的评估凝血因子高于血浆组（P<0.02）。两组的安全性特征（不良事件、严重不良事件、血栓栓塞事件和死亡）相似；4F-PCC 组 103 例患者中有 66 例（4F-PCC 组）和血浆组 109 例患者中有 71 例（血浆组）发生≥1 例不良事件。
结论
4F-PCC 是维生素 K 拮抗剂大出血事件紧急逆转的有效替代物，临床评估出血和实验室测量 INR 和因子水平均证明了这一点。
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