Lu Genmin, Conley Pamela B, Leeds Janet M, Karbarz Mark J, Levy Gallia G, Mathur Vandana S, Castillo Janice, Crowther Mark, Curnutte John T
Portola Pharmaceuticals, Inc., South San Francisco, CA.
Mathur Consulting, San Francisco, CA; and.
Blood Adv. 2020 Feb 25;4(4):728-739. doi: 10.1182/bloodadvances.2019000885.
As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).
与任何抗凝剂一样，凝血因子Xa（FXa）抑制剂与严重出血风险相关。安多凝血素α是一种缺乏酶活性的重组修饰人FXa，用于逆转FXa抑制剂引起的抗凝作用。在两项2期、随机、双盲、安慰剂对照、单中心研究中，在使用利伐沙班或依度沙班进行治疗性抗凝后，将不同方案的安多凝血素α给予健康志愿者，并评估多个抗凝逆转和安全性终点。安多凝血素α迅速且有效地逆转了利伐沙班和依度沙班的抗凝作用。推注后2分钟内，抗FXa活性显著降低，与安慰剂相比，最大降幅分别约为93%（P <.05）和82%（P <.05）。在抗FXa活性最大逆转时，安多凝血素α与总抗凝剂的化学计量比，利伐沙班为1:1至1.3:1，依度沙班为1.41:1至2.58:1。与安慰剂相比，当安多凝血素α作为推注或推注后持续输注给药时，观察到给药完成后凝血酶生成持续正常化约2小时，未结合抗凝剂持续降低（最大约80%）长达约4小时。安多凝血素α耐受性良好，未发生严重不良事件或血栓形成事件。安多凝血素α已在美国和欧洲获批，用于逆转接受利伐沙班或阿哌沙班治疗且发生危及生命或无法控制出血的患者的抗凝作用。这些研究已在clinicaltrials.gov上注册（#NCT03578146和#NCT03551743）。
