Candidate drugs for preventive treatment of unruptured intracranial aneurysms: A cross-sectional study.

Kampei Shimizu,Hiroharu Kataoka,Chiaki Sakai,Susumu Miyamoto,Nobuyuki Sakai,Tomohiro Aoki,Shoichi Tani,Hirotoshi Imamura,Hidemitsu Adachi,Akira Ishii,Jinglu Ai

doi:10.1371/journal.pone.0246865

Kampei Shimizu, Hiroharu Kataoka + Show 9 more

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https://doi.org/10.1371/journal.pone.0246865

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Abstract

Background and purposeEstablishment of drug therapy to prevent rupture of unruptured intracranial aneurysms (IAs) is needed. Previous human and animal studies have gradually clarified candidate drugs for preventive treatment of IA rupture. However, because most of these candidates belong to classes of drugs frequently co-administered to prevent cardiovascular diseases, epidemiological studies evaluating these drugs simultaneously should be performed. Furthermore, because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials.Materials and methodsWe performed a cross-sectional study enrolling patients diagnosed with IAs between July 2011 and June 2019 at our institution. Patients were divided into ruptured or unruptured groups. The drugs investigated were selected according to evidence suggested by either human or animal studies. Univariate and multivariate logistic regression analyses were performed to assess the association of drug treatment with rupture status. We also performed drug-by-drug assessments of the association, including dose-response relationships, with rupture status.ResultsIn total, 310 patients with ruptured and 887 patients with unruptured IAs were included. Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38–0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30–0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48–0.93) with ruptured IAs. Moreover, inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipine, cilnidipine, and amlodipine among calcium channel blockers, and valsartan, azilsartan, candesartan, and olmesartan among ARBs. Only non-aspirin non-steroidal anti-inflammatory drugs were positively associated with ruptured IAs (OR, 3.24; 95% CI 1.71–6.13).ConclusionsThe present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for preventive treatment of unruptured IAs.

Highlights

Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38–0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30–0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48–0.93) with ruptured intracranial aneurysms (IAs)
Inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipine, cilnidipine, and amlodipine among calcium channel blockers, and valsartan, azilsartan, candesartan, and olmesartan among
The present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for preventive treatment of unruptured IAs

Summary

Introduction

Preventive treatment by neurosurgical or endovascular intervention has been applied for patients with unruptured intracranial aneurysms (IAs) when the estimated rupture rate outweighed the risk of complications associated with these modalities; otherwise, patients were untreated and observed by serial imaging [1]. More recent studies have reproduced these findings with a higher volume of cases and using multivariate analyses with propensity score weighting [4, 5] Because these results are consistent with the evidence acquired from animal studies [6, 7], the development of drug therapy for unruptured IAs has become more feasible. Because most of the drugs proposed far are typically used to prevent cardiovascular diseases, these drugs are frequently co-administered in a single patient [2,3,4,5, 8] Observational studies evaluating these drugs simultaneously should be useful to assess the association with rupture status more precisely. Because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials

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