Fukuda Shunichi, Niwa Youko, Ren Nice, Yonemoto Naohiro, Kasahara Masato, Yasaka Masahiro, Ezura Masayuki, Asai Takumi, Miyazono Masayuki, Korai Masaaki, Tsutsumi Keisuke, Shigeta Keigo, Oi Yuta, Nishimura Ataru, Fukuda Hitoshi, Goto Masanori, Yoshida Takashi, Fukuda Miyuki, Yasoda Akihiro, Iihara Koji
1Department of Neurosurgery and.
2Next-Generational Research for Stroke and Heart Disease and.
J Neurosurg. 2024 Oct 25;142(3):676-683. doi: 10.3171/2024.6.JNS24714. Print 2025 Mar 1.
Rupture of cerebral aneurysms has a poor prognosis, and growing aneurysms are prone to rupture. Although the number of coil embolization procedures is increasing worldwide, they are more prone to recurrence than clipping surgeries. However, there is still no drug that prevents aneurysm growth or recanalization after coil embolization. The authors have previously focused on the role of hemodynamics in cerebral aneurysm development and reported that inhibition of the P2X4 purinoceptor, by which vascular endothelial cells sense blood flow, reduced the induction and growth of aneurysms in an animal model. In this study, the authors investigated the effects of paroxetine, a P2X4 inhibitor also used as an antidepressant, on aneurysm growth and recanalization after endovascular coiling.
Using the J-ASPECT Study registry, the largest comprehensive reimbursement database system for acute stroke inpatient care in Japan, the authors searched for patients incidentally taking paroxetine who were registered in the decade 2010-2019 with an unruptured cerebral aneurysm or who underwent aneurysm coiling. They calculated the growth incidence and growth rate by the person-year method and the odds ratio for recanalization within 1 year after coiling and statistically compared to controls.
Seventy-eight stroke facilities participated, and 275 patients were identified as potentially eligible. Thirty-seven patients with unruptured aneurysms and 38 after coil embolization met all eligibility criteria. They were compared with 396 control cases of unruptured aneurysms and 308 coil-placement controls. Multivariate analysis showed that paroxetine significantly reduced the incidence of aneurysm growth (number of cases with growth/person/year; incidence rate ratio [IRR] 0.24, 95% CI 0.05-0.66; p = 0.003) and the growth rate (total increase in maximum diameter in millimeters/person/year; IRR 0.57, 95% CI 0.28-0.98; p = 0.04). Paroxetine also significantly reduced the odds of recanalization in the year after coiling (OR 0.21, 95% CI 0.05-0.95; p = 0.04). The authors then performed propensity score matching to reduce bias due to imbalances in patient characteristics between the two groups; the outcome confirmed that paroxetine significantly reduced aneurysm growth incidence (IRR 0.02, 95% CI 0.008-0.05; p < 0.0001) and growth rate (IRR 0.03, 95% CI 0.01-0.06; p < 0.0001) and the 1-year recanalization (OR 0.18, 95% CI 0.03-0.99; p = 0.04).
This observational cohort study suggests that P2X4 inhibitors such as paroxetine may be clinically applicable as prophylaxis against aneurysm rupture and postoperative recanalization.
脑动脉瘤破裂预后较差，且不断增大的动脉瘤易于破裂。尽管全球范围内弹簧圈栓塞手术的数量在增加，但与夹闭手术相比，其更容易复发。然而，目前仍没有药物能够预防弹簧圈栓塞术后动脉瘤的生长或再通。作者此前关注了血流动力学在脑动脉瘤发展中的作用，并报告称，抑制P2X4嘌呤受体（血管内皮细胞借此感知血流）可减少动物模型中动脉瘤的诱发和生长。在本研究中，作者调查了帕罗西汀（一种也用作抗抑郁药的P2X4抑制剂）对血管内栓塞术后动脉瘤生长和再通的影响。
作者利用日本最大的急性卒中住院患者综合报销数据库系统J-ASPECT研究登记处，搜索了2010 - 2019年期间登记的偶然服用帕罗西汀的未破裂脑动脉瘤患者或接受动脉瘤栓塞治疗的患者。他们采用人年法计算生长发生率和生长速率以及栓塞后1年内再通的比值比，并与对照组进行统计学比较。
78家卒中机构参与研究，确定了275例可能符合条件的患者。37例未破裂动脉瘤患者和38例弹簧圈栓塞术后患者符合所有入选标准。将他们与396例未破裂动脉瘤对照病例和308例弹簧圈置入对照病例进行比较。多变量分析显示，帕罗西汀显著降低了动脉瘤生长的发生率（生长病例数/人/年；发病率比[IRR] 0.24，9５%可信区间0.05 - 0.66；p = 0.003）和生长速率（最大直径毫米数的总增加量/人/年；IRR 0.57，95%可信区间0.28 - 0.98；p = 0.04）。帕罗西汀还显著降低了栓塞后1年内再通的几率（OR 0.21，95%可信区间0.05 - 0.95；p = 0.04）。然后作者进行倾向评分匹配以减少两组患者特征不平衡导致的偏倚；结果证实，帕罗西汀显著降低了动脉瘤生长发生率（IRR 0.02，95%可信区间0.008 - 0.05；p < 0.0001）和生长速率（IRR 0.03，95%可信区间0.01 - 0.06；p < 0.0001）以及1年再通率（OR 0.18，95%可信区间0.03 - 0.99；p = 0.04）。
这项观察性队列研究表明，帕罗西汀等P2X4抑制剂可能在临床上适用于预防动脉瘤破裂和术后再通。
