Fibrinogen replacement to prevent intracranial hemorrhage in ischemic stroke patients after thrombolysis – a prospective randomized open blinded endpoint trial (FibER): rationale and methods

IF 2.1 4区医学 Q3 NEUROSCIENCES

Journal of Stroke & Cerebrovascular Diseases Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI:10.1016/j.jstrokecerebrovasdis.2026.108572

Andrea Zini , Laura Vandelli , Stefano Forlivesi , Elena Merli , Ludovica Migliaccio , Luana Gentile , Michele Romoli , Flavia Baccari , Mario Sebastiani , Francesco Nonino , Sabina Cevoli , Guido Bigliardi

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引用次数: 0

Abstract

Rationale

Fibrinogen depletion happens soon after intravenous thrombolysis (IVT) for acute ischemic stroke, in relation to the suboptimal affinity of recombinant tissue plasminogen activator (rtPA) to thrombus fibrin. Fibrinogen depletion carries a 4-fold increase in risk of bleeding after IVT.

Aim

FibER will determine if early fibrinogen repletion through intravenous infusion of fibrinogen (2 g) in case of fibrinogen depletion is safe and can prevent bleeding after IVT.

Sample size estimates

The sample size was calculated assuming a combined rate of parenchymal hematoma at the CT scan in the treated group of 3% versus a 14% rate in the control group, for an overall absolute difference of 11%. Considering such a difference among groups, a 1:1 allocation of treatment will provide 100 patients per group to reach an 80% power to detect a statistically significant difference (p<0.05).

Methods and design

Two-center phase 3 prospective randomized open blinded endpoint (PROBE) trial. Fibrinogen depletion is defined as a decrease of serum fibrinogen level <200 mg/dl and/or a decrease of >50% from baseline level after 2 and/or 6 hours from IVT. Patients will be randomized to receive fibrinogen infusion (2 g) versus no fibrinogen infusion at the moment of fibrinogen depletion identification.

Study outcomes

The primary outcome is intracranial hemorrhage, defined as parenchymal hematoma after 24 hours and 7 days from IVT. Subgroup analysis according to the severity of fibrinogen depletion is planned. Secondary outcomes will include: symptomatic intracerebral hemorrhage, extracranial bleeding of any type, NIHSS at baseline and after 7 days, modified Rankin Scale at 3 months, serious thromboembolic adverse events (including deep vein thrombosis, pulmonary embolism, myocardial infarct, recurrence of ischemic stroke, major cardiovascular events), and prevalence of hyperfibrinolysis (ROTEM-based definition).

Discussion

FibER will determine if early fibrinogen repletion is safe during acute ischemic stroke and prevent bleeding in patients with fibrinogen depletion after IVT for acute ischemic stroke (registered with US National Library of Medicine NCT05300672 and Eudra-CT 2020-005242-41).

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纤维蛋白原替代预防缺血性脑卒中患者溶栓后颅内出血——一项前瞻性随机开放盲法终点试验（FibER）：理论基础和方法

理论依据：急性缺血性卒中静脉溶栓（IVT）治疗后，纤维蛋白原消耗很快发生，这与重组组织型纤溶酶原激活剂（rtPA）对血栓纤维蛋白的亲和力不佳有关。纤维蛋白原耗竭会使IVT后出血风险增加4倍。目的：通过静脉输注纤维蛋白原（2g），在纤维蛋白原耗尽的情况下，确定早期纤维蛋白原补充是否安全，是否能预防IVT后出血。样本量估计：样本量的计算假设治疗组CT扫描的实质血肿合并率为3%，对照组为14%，总体绝对差为11%。考虑到组间的差异，1:1的治疗分配将为每组提供100例患者，以达到80%的检测统计学显著差异的能力（方法和设计：两中心3期前瞻性随机开放盲法终点（PROBE）试验）。纤维蛋白原消耗定义为静脉注射后2和/或6小时血清纤维蛋白原水平较基线水平下降50%。患者将被随机分配接受纤维蛋白原输注（2g）和不输注纤维蛋白原在纤维蛋白原耗尽的时刻。研究结果：主要结果为颅内出血，定义为IVT后24小时和7天的实质血肿。计划根据纤维蛋白原耗竭的严重程度进行亚组分析。次要结局将包括：有症状的脑出血、任何类型的颅外出血、基线和7天后的NIHSS、3个月时的改良Rankin量表、严重的血栓栓塞不良事件（包括深静脉血栓形成、肺栓塞、心肌梗死、缺血性卒中复发、主要心血管事件）和高纤溶的患病率（基于rotem的定义）。讨论：FibER将确定急性缺血性卒中期间早期纤维蛋白原补充是否安全，并预防急性缺血性卒中IVT后纤维蛋白原消耗患者出血（已在美国国家医学图书馆NCT05300672和Eudra-CT 2020-005242-41注册）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Stroke & Cerebrovascular Diseases Medicine-Surgery

CiteScore

5.00

自引率

4.00%

发文量

583

审稿时长

62 days

期刊介绍： The Journal of Stroke & Cerebrovascular Diseases publishes original papers on basic and clinical science related to the fields of stroke and cerebrovascular diseases. The Journal also features review articles, controversies, methods and technical notes, selected case reports and other original articles of special nature. Its editorial mission is to focus on prevention and repair of cerebrovascular disease. Clinical papers emphasize medical and surgical aspects of stroke, clinical trials and design, epidemiology, stroke care delivery systems and outcomes, imaging sciences and rehabilitation of stroke. The Journal will be of special interest to specialists involved in caring for patients with cerebrovascular disease, including neurologists, neurosurgeons and cardiologists.