Milling Truman J, Middeldorp Saskia, Xu Lizhen, Koch Bruce, Demchuk Andrew, Eikelboom John W, Verhamme Peter, Cohen Alexander T, Beyer-Westendorf Jan, Gibson C Michael, Lopez-Sendon Jose, Crowther Mark, Shoamanesh Ashkan, Coppens Michiel, Schmidt Jeannot, Albaladejo Pierre, Connolly Stuart J
Seton Dell Medical School Stroke Institute, Dell Medical School, University of Texas at Austin (T.J.M.).
Department of Internal Medicine and Radboud Institute of Health Sciences, Nijmegen, the Netherlands (S.M.).
Circulation. 2023 Mar 28;147(13):1026-1038. doi: 10.1161/CIRCULATIONAHA.121.057844. Epub 2023 Feb 20.
Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented.
Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome.
There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted =0.022; unadjusted =0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors.
In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.
URL: https://www.
gov; Unique identifier: NCT02329327.
andexanet alfa是一种经过改良的重组无活性Xa因子（FXa），旨在逆转FXa抑制剂的作用。ANNEXA - 4（andexanet alfa，一种新型Xa因子抑制剂抗凝作用解毒剂）是一项多中心、前瞻性、3b/4期单组队列研究，评估了andexanet alfa在急性大出血患者中的应用。现将最终分析结果公布。
纳入在使用FXa抑制剂后18小时内发生急性大出血的患者。共同主要终点为andexanet alfa治疗期间抗FXa活性相对于基线的变化，以及12小时时根据先前逆转研究中使用的量表定义的良好或优异止血疗效。疗效人群包括基线抗FXa活性水平高于预定义阈值（阿哌沙班和利伐沙班≥75 ng/mL，依度沙班≥40 ng/mL，依诺肝素≥0.25 IU/mL；以用于校准物的相同单位报告）且经判定符合大出血标准（改良国际血栓与止血学会定义）的患者。安全人群包括所有患者。主要出血标准、止血疗效、血栓事件（根据预防性[即较低剂量，用于预防而非治疗]或全剂量口服抗凝重新开始之前或之后发生进行分层）和死亡情况由独立判定委员会进行评估。基线和整个随访期内的内源性凝血酶潜力中位数为次要结局。
共纳入479例患者（平均年龄78岁；54%为男性；86%为白人）；81%因心房颤动接受抗凝治疗，自末次给药后的中位时间为11.4小时，其中245例（51%）使用阿哌沙班，176例（37%）使用利伐沙班，36例（8%）使用依度沙班，22例（5%）使用依诺肝素。出血主要为颅内出血（n = 331 [69%]）或胃肠道出血（n = 109 [23%]）。在可评估的阿哌沙班患者（n = 172）中，抗FXa活性中位数从146.9 ng/mL降至10.0 ng/mL（降低93% [95% CI，94 - 93]）；在利伐沙班患者（n = 132）中，从214.6 ng/mL降至10.8 ng/mL（94% [95% CI，95 - 93]）；在依度沙班患者（n = 28）中，从121.1 ng/mL降至24.4 ng/mL（71% [95% CI，82 - 65]）；在依诺肝素患者（n = 17）中，从0.48 IU/mL降至0.11 IU/mL（75% [95% CI，79 - 67]）。342例可评估患者中有274例（80% [95% CI，75 - 84]）实现了良好或优异止血。在安全人群中，50例（10%）患者发生血栓事件；其中16例在出血事件后开始的预防性抗凝治疗期间发生。重新开始口服抗凝治疗后未发生血栓事件。对于特定人群，从基线到最低点抗FXa活性的降低显著预测了颅内出血患者的止血疗效（受试者工作特征曲线下面积，0.62 [95% CI，0.54 - 0.70]），并且与75岁以下患者较低的死亡率相关（校正后 = 0.022；未校正 = 0.003）。对于所有FXa抑制剂，在andexanet alfa推注结束至24小时内，内源性凝血酶潜力中位数均在正常范围内。
在与使用FXa抑制剂相关的大出血患者中，andexanet alfa治疗可降低抗FXa活性，80%的患者具有良好或优异的止血疗效。
网址：https://www.
gov；唯一标识符：NCT02329327。
