Ospel Johanna M, Goyal Mayank, Menon Bijoy K, Almekhlafi Mohammed A, Zerna Charlotte, Nogueira Raul G, McTaggart Ryan A, Demchuk Andrew M, Poppe Alexandre Y, Rempel Jeremy L, Joshi Manish, Kashani Nima, Heard Kathy, Field Thalia S, Dowlatshahi Darius, van Adel Brian, Swartz Richard H, Shah Ruchir, Sauvageau Eric, Puetz Volker, Silver Frank L, Campbell Bruce, Chapot René, Tymianski Michael, Hill Michael D
Department of Diagnostic Imaging (J.M.O., M.G., B.K.M., M.A.A., A.M.D., M.J., M.D.H.), University of Calgary, Alberta, Canada.
Department of Clinical Neurosciences (J.M.O., M.G., B.K.M., M.A.A., A.M.D., M.D.H.), University of Calgary, Alberta, Canada.
Stroke. 2025 Jan;56(1):14-21. doi: 10.1161/STROKEAHA.124.048601. Epub 2024 Dec 9.
In the ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke), treatment with nerinetide was associated with a smaller infarct volume among patients who did not receive intravenous alteplase. We assessed the effect of nerinetide on the surrogate imaging outcome of final infarct volume in patients who did not receive intravenous alteplase and explored predictors of outcome and modifiers of nerinetide's effect on infarct volume.
ESCAPE-NA1 was a multicenter, randomized trial in which patients with acute stroke with a baseline Alberta Stroke Program Early CT Score >4, undergoing endovascular thrombectomy, were randomized to receive intravenous nerinetide or placebo. Patients not receiving intravenous alteplase were included in this post hoc secondary analysis of the trial data. Final infarct volume was manually segmented on 24-hour noncontrast computed tomography or diffusion-weighted magnetic resonance imaging. Predictors of final infarct volume were identified using multivariable linear regression with cubic-root-transformed infarct volume as the dependent variable. Evidence of treatment-by-predictor interaction was tested by including interaction terms in the model.
Four hundred forty-six patients (219 who received nerinetide and 227 who received a placebo) out of a total of 1105 enrolled patients were included in this secondary post hoc analysis of the randomized ESCAPE-NA1 trial. Nerinetide was a strong predictor of smaller infarct volume (adjusted β coefficient, -0.35 [95% CI, -0.67 to -0.02]). Other predictors of smaller infarct volume were history of hypertension, good pial collateral filling on multiphase computed tomography angiography, a middle cerebral artery occlusion compared with an internal carotid artery occlusion, lower baseline National Institutes of Health Stroke Scale score, lower baseline systolic blood pressure, lower baseline serum glucose, shorter onset-to-randomization time, and higher Alberta Stroke Program Early CT Score. There was evidence of a treatment-by-systolic blood pressure and treatment-by-anesthesia interaction: nerinetide attenuated the negative effects of elevated baseline (=0.02) and postdose (=0.04) systolic blood pressure and use of general anesthesia (=0.06) on final infarct volume. We observed a marginally significant interaction with reperfusion status, such that nerinetide may attenuate the harmful effect of poor reperfusion status on infarct volume (=0.08).
Nerinetide treatment was strongly associated with smaller final infarct volumes among patients not cotreated with alteplase. The reduction in infarct volume was greater among patients with poor prognostic factors.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02930018.
在ESCAPE-NA1试验（神经保护剂治疗急性缺血性卒中的疗效和安全性）中，未接受静脉注射阿替普酶的患者使用神经保护剂治疗后梗死体积较小。我们评估了神经保护剂对未接受静脉注射阿替普酶患者最终梗死体积这一替代成像结局的影响，并探讨了结局的预测因素以及神经保护剂对梗死体积影响的调节因素。
ESCAPE-NA1是一项多中心随机试验，急性卒中且阿尔伯塔卒中项目早期CT评分>4分、接受血管内血栓切除术的患者被随机分配接受静脉注射神经保护剂或安慰剂。未接受静脉注射阿替普酶的患者纳入该试验数据的事后二次分析。在24小时非增强计算机断层扫描或扩散加权磁共振成像上手动分割最终梗死体积。使用多变量线性回归确定最终梗死体积的预测因素，以立方根转换后的梗死体积作为因变量。通过在模型中纳入交互项来检验治疗与预测因素交互作用的证据。
在随机分组的ESCAPE-NA1试验的1105名入组患者中，共有446名患者（219名接受神经保护剂治疗，227名接受安慰剂治疗）纳入此次事后二次分析。神经保护剂是梗死体积较小的有力预测因素（调整后的β系数为-0.35[95%CI，-0.67至-0.02]）。梗死体积较小的其他预测因素包括高血压病史、多期计算机断层扫描血管造影显示软脑膜侧支循环良好、大脑中动脉闭塞相较于颈内动脉闭塞、较低的基线美国国立卫生研究院卒中量表评分、较低的基线收缩压、较低的基线血清葡萄糖、较短的发病至随机分组时间以及较高的阿尔伯塔卒中项目早期CT评分。有证据表明存在收缩压与治疗以及麻醉与治疗的交互作用：神经保护剂减弱了基线收缩压升高（P=0.02）和给药后收缩压升高（P=0.04）以及全身麻醉（P=0.06）对最终梗死体积的负面影响。我们观察到与再灌注状态存在边缘显著的交互作用，即神经保护剂可能减弱再灌注状态不佳对梗死体积的有害影响（P=0.08）。
在未联合使用阿替普酶治疗的患者中，神经保护剂治疗与最终梗死体积较小密切相关。预后因素较差的患者梗死体积减小更为明显。
