Abstract：
Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts.
In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug.
Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]).
These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials.
URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.
In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug.
Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]).
These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials.
URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.
摘要：
■2期PACIFIC-Stroke（口服复方BAY2433334-非心源性卒中通过抑制FXIa的抗凝方案）随机试验的探索性分析表明，asundexian，口服因子XIa抑制剂，预防动脉粥样硬化性卒中患者的复发性卒中和短暂性脑缺血发作。在这份事后探索性分析中，我们假设asundexian在大型，多个,磁共振成像显示的皮质急性梗死或皮质急性梗死，asundexian会防止皮层隐秘梗塞。
■在这项安慰剂对照双盲随机对照试验中，轻度至中度非心源性栓塞性缺血性卒中患者被分配至阿松地安组(每日一次10、20或50mg)或安慰剂组,除了抗血小板治疗。在随机化的72小时内需要进行脑磁共振成像，并在26周或停药研究药物时重复。
■在1808名随机患者中，1780（98.5%）有可解释的基线磁共振成像，其中1628例(91.5%)出现≥1例弥散加权成像阳性急性梗死.1439例患者获得磁共振成像随访,其中1358人在试验期间无症状性卒中.与安慰剂相比，asundexian每天50mg赋予了降低复发性缺血性卒中或偶发隐性梗死风险的趋势(风险比，0.71[95%CI，0.45-1.11]）和复发性缺血性卒中或短暂性脑缺血发作（次要结果；风险比，0.59[95%CI，0.33-1.06]），在单个小皮质下梗死患者中并不明显（风险比，1.14[95%CI，0.62-2.10]和0.93[95%CI，0.28-3.06]）。服用asundexian50mg的患者减少了皮层隐性梗塞的发生率，但差异无统计学意义(粗发病率，0.56[95%CI，0.28-1.12]）。
■这些探索性的，未经证实的结果表明，asundexian可以预防新的栓塞性梗塞，但不能预防小动脉闭塞。隐性脑梗塞亚型对抗凝预防反应不同的假设应在未来的试验中进行测试。
URL：https://clinicaltrials.gov；唯一标识符：NCT04304508。
■在这项安慰剂对照双盲随机对照试验中，轻度至中度非心源性栓塞性缺血性卒中患者被分配至阿松地安组(每日一次10、20或50mg)或安慰剂组,除了抗血小板治疗。在随机化的72小时内需要进行脑磁共振成像，并在26周或停药研究药物时重复。
■在1808名随机患者中，1780（98.5%）有可解释的基线磁共振成像，其中1628例(91.5%)出现≥1例弥散加权成像阳性急性梗死.1439例患者获得磁共振成像随访,其中1358人在试验期间无症状性卒中.与安慰剂相比，asundexian每天50mg赋予了降低复发性缺血性卒中或偶发隐性梗死风险的趋势(风险比，0.71[95%CI，0.45-1.11]）和复发性缺血性卒中或短暂性脑缺血发作（次要结果；风险比，0.59[95%CI，0.33-1.06]），在单个小皮质下梗死患者中并不明显（风险比，1.14[95%CI，0.62-2.10]和0.93[95%CI，0.28-3.06]）。服用asundexian50mg的患者减少了皮层隐性梗塞的发生率，但差异无统计学意义(粗发病率，0.56[95%CI，0.28-1.12]）。
■这些探索性的，未经证实的结果表明，asundexian可以预防新的栓塞性梗塞，但不能预防小动脉闭塞。隐性脑梗塞亚型对抗凝预防反应不同的假设应在未来的试验中进行测试。
URL：https://clinicaltrials.gov；唯一标识符：NCT04304508。
