确定有效测试神经保护药物的目标人群

确定有效测试神经保护药物的目标人群

摘要

背景和目的：我们的目的是利用基线结果预测因子来确定受益于潜在神经保护药物的可能性更高的急性缺血性卒中患者亚组，并测试不同的选择标准策略是否可以提高检测到的治疗效果。

方法：我们分析了接受血管内治疗的急性脑卒中患者出院/第5天时，24-72小时计算机断层扫描测量的最终梗死体积（FIV）与美国国立卫生研究院卒中量表之间的关系。模型根据年龄、性别和受累半球进行调整。我们分析了美国国立卫生研究院卒中量表中绝对（5-15ml）和相对（33%）FIV降低对整个人群以及根据CT灌注成像基线标准选择的不同亚组患者的影响。

结果：我们分析了627例患者，FIV与5天美国国立卫生研究院卒中量表之间的相关性最好用二次函数来描述，在调整分析中回归系数β=1.56（[95%CI，1.45-1.67]P<0.001）。在考虑固定绝对（5/15ml）FIV降低的模型中，排除预测FIV较大的患者时，治疗效果最高，而在33%FIV降低模型中，排除预期良好结果的患者时，治疗效果增加。

结论：在脑卒中神经保护药物试验中，无论是血管内血栓切除术后疗效良好的患者还是大面积梗死的患者，都可能会降低治疗效果。入院时的计算机断层扫描灌注有助于根据预期的药物效果选择合适的患者。

Stroke

. 2021 Jan;52(2):505-510. doi: 10.1161/STROKEAHA.120.032025. Epub 2021 Jan 11.

Defining a Target Population to Effectively Test a Neuroprotective Drug

Marta Olivé-Gadea 1 2, Manuel Requena 1 2, Daniel Campos 1 2, Alvaro Garcia-Tornel 1 2, Matías Deck 1 2, Marian Muchada 1 2, Sandra Boned 1 2, Noelia Rodríguez 1 2, Jesús Juega 1 2, David Rodríguez-Luna 1 2, Jorge Pagola 1 2, Marta Rubiera 1 2, Macarena Hernández-Jiménez 3, Carlos A Molina 1 2, Marc Ribo 1 2

Affiliations collapse

Affiliations

1Stroke Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain (M.O.-G., M. Requena, D.C., A.G.-T., M.D., M.M., S.B., N.R., J.J., D.R.-L., J.P., M. Rubiera, C.A.M., M. Ribo).

2Departament de Medicina, Universitat Autònoma de Barcelona, Spain (M.O.-G., M. Requena, D.C., A.G.-T., M.D., M.M., S.B., N.R., J.J., D.R.-L., J.P., M. Rubiera, C.A.M., M. Ribo).

3Apta Targets, Madrid, Spain (M.H.-J.).

PMID: 33423513 DOI: 10.1161/STROKEAHA.120.032025

Abstract

Background and purpose: We aim to identify the subgroup of acute ischemic stroke patients with higher probabilities of benefiting from a potential neuroprotective drug using baseline outcome predictors and test whether different selection criteria strategies can improve detected treatment effect.

Methods: We analyzed the association between final infarct volume (FIV), measured on 24- to 72-hour computed tomography, and National Institutes of Health Stroke Scale at discharge/day 5 of acute stroke patients who underwent endovascular treatment. Models were adjusted for age, sex, and affected hemisphere. We analyzed the impact of absolute (5-15 mL) and relative (33%) FIV reductions in the National Institutes of Health Stroke Scale in the whole population and in different subsets of patients selected according to baseline imaging criteria using computed tomography perfusion.

Results: We analyzed 627 patients; association between FIV and 5-day National Institutes of Health Stroke Scale was best described with a quadratic function, with a regression coefficient β=1.56 ([95% CI, 1.45-1.67] P<0.001) in the adjusted analysis. In the models considering a fixed absolute (5/15 mL) FIV reduction, treatment effect was highest when patients with predicted larger FIV were excluded, whereas in a 33% FIV reduction model, treatment effect increased with the exclusion of patients with expected excellent outcomes.

Conclusions: Patients either with excellent outcomes after endovascular thrombectomy or with large infarcts may dilute the treatment effect in stroke neuroprotective drug trials. Computed tomography perfusion on admission may help selecting adequate patients according to expected drug effect profile.

Keywords: infarction; ischemia; neuroprotection; patient selection; probability.