依达赛珠单抗治疗因子 Xa 抑制剂相关急性脑出血。
Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.
机构信息
From the Population Health Research Institute, McMaster University, Hamilton, ON (S.J.C., M.S., M.C., A.T., T.K., L.X., K.T., A.S.), and the Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB (A.M.D.) - both in Canada; Guy's and St. Thomas' Hospital, King's College London (A.T.C.), and Imperial College (R.V.), London, NIHR Biomedical Research Centre and College of Life Sciences, University of Leicester, Leicester (T.G.R.), and Alexion Pharmaceuticals UK, Uxbridge (A.L.) - all in the United Kingdom; the Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland (A.C.); the Department of Clinical Sciences Lund, Neurology, Lund University, and the Department of Neurology, Skåne University Hospital, Lund (A.G.L.), and AstraZeneca Biopharmaceuticals Research and Development, Late-stage Development, Cardiovascular, Renal, and Metabolism, Gothenburg (A.H., P.L., M.K., E.E.) - all in Sweden; Vall d'Hebron University Hospital, Barcelona (C.A.M.); Semmelweis University, Budapest, Hungary (D.B.); Sapienza University of Rome, Rome (D. Toni); the Department of Neurology, Inselspital University Hospital and University of Bern, Bern, Switzerland (D.J.S.); Rambam Health Care Campus, Technion, Israel Institute of Technology, Haifa (D. Tanne); the Department of Neurology, Oslo University Hospital, and the Norwegian Air Ambulance Foundation - both in Oslo (E.C.S.); the Second Department of Neurology, National and Kapodistrian University of Athens, "Attikon" University Hospital, Athens (G.T.); Copenhagen University Hospital, Bispebjerg Hospital, Copenhagen (H.C.); the Department of Medicine 1, Division "Thrombosis and Hemostasis," University Hospital Dresden, Dresden (J.B.-W.), Alfried Krupp Krankenhaus, Essen (R.V.), the Department of Neurology and Stroke (S.P.) and the Hertie Institute for Clinical Brain Research (S.P.), Eberhard-Karls University, Tübingen, the Department of Neurology, Universitätsklinikum Erlangen, Erlangen (B.K.), and the Department of Neurology, Heidelberg University Hospital, Heidelberg (C.G.) - all in Germany; the Department of Neurology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam (J.M.C.), and Radboud University Medical Center, Nijmegen (S.M.) - both in the Netherlands; University Hospitals Leuven, University of Leuven (P.V.), the Department of Neurosciences and Experimental Neurology, KU Leuven (R.L.), and the Department of Neurology, University Hospitals Leuven (R.L.) - all in Leuven, Belgium; Bichat Claude-Bernard Hospital, Paris (P.A.); Turku University Hospital, Turku, Finland (R.O.R.); Tomas Bata Regional Hospital, Zlín, Czech Republic (R.M.); Dell Medical School, University of Texas, Austin, and the University of Houston, Houston (T.J.M.); University of Porto, Porto, Portugal (V.T.-C.); and Hospital of St. John of God, Sigmund Freud University, Medical Faculty, Vienna (W.L.).
出版信息
N Engl J Med. 2024 May 16;390(19):1745-1755. doi: 10.1056/NEJMoa2313040.
BACKGROUND
Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied.
METHODS
We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death.
RESULTS
A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days.
CONCLUSIONS
Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).
背景
正在服用因子 Xa 抑制剂的急性脑出血患者有血肿扩大的风险。逆转因子 Xa 抑制剂作用的andexanet alfa 对血肿体积扩大的影响尚未得到很好的研究。
方法
我们以 1:1 的比例随机分配在急性脑出血发生前 15 小时内服用过因子 Xa 抑制剂的患者接受andexanet 或常规护理。主要终点是止血效果，定义为基线后 12 小时血肿体积增加 35%或以下，12 小时内国家卫生研究院卒中量表评分增加小于 7 分（评分范围为 0 至 42 分，分数越高表示神经功能缺损越严重），并且在 3 小时至 12 小时之间未接受挽救性治疗。安全性终点是血栓事件和死亡。
结果
共有 263 名患者被分配接受 andexanet，267 名患者接受常规护理。在包括 452 名患者的中期分析中评估了疗效，对所有 530 名入组患者进行了安全性分析。房颤是使用因子 Xa 抑制剂的最常见指征。在接受常规护理的患者中，85.5%接受了凝血酶原复合物浓缩物。andexanet 治疗的 224 名患者中有 150 名（67.0%）和接受常规护理的 228 名患者中有 121 名（53.1%）达到止血效果（调整差异，13.4 个百分点；95%置信区间[CI]，4.6 至 22.2；P=0.003）。andexanet 治疗的患者从基线到 1 至 2 小时最低点的抗因子 Xa 活性中位数降低了 94.5%，而常规护理组为 26.9%（P<0.001）。接受 andexanet 的 263 名患者中有 27 名（10.3%）和接受常规护理的 267 名患者中有 15 名（5.6%）发生血栓事件（差异，4.6 个百分点；95%CI，0.1 至 9.2；P=0.048）；缺血性卒中分别发生在 17 名患者（6.5%）和 4 名患者（1.5%）。两组患者在改良 Rankin 量表评分或 30 天内死亡方面无明显差异。
结论
在接受因子 Xa 抑制剂治疗的脑出血患者中，andexanet 与常规护理相比，可更好地控制血肿扩大，但与血栓事件有关，包括缺血性卒中。（由 Alexion AstraZeneca 罕见病和其他机构资助；ANNEXA-I ClinicalTrials.gov 编号，NCT03661528）。
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