Patient population

This study will include 484 patients (two treatment groups with a 1:1 randomization ratio) with RAs receiving EVT within 72 h of onset and receiving preoperative administration of 200 mg aspirin. Fig 1 presents a flowchart of the study.

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Fig 1. Study flowchart.

AEs, adverse events; AG, angiography; CT, computed tomography; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; EVT, endovascular treatment; RAs, ruptured aneurysms.

https://doi.org/10.1371/journal.pone.0310906.g001

The inclusion criteria are as follows:

1. RAs in the acute phase
2. Aneurysm embolization scheduled within 72 h of onset
3. Age ≥20 years at the time of onset
4. Written informed consent obtained from the patient or their legally acceptable representative (e.g., spouse, parent, or adult child) for participation in the study

The exclusion criteria are as follows:

1. Pre-stroke modified Rankin Scale (mRS) score ≥4, indicating dependence in daily activities before the onset of the current illness
2. Dissecting aneurysm scheduled for parent artery occlusion
3. Rupture of recurrent aneurysms following EVT
4. Rupture of aneurysms associated with cerebral arteriovenous malformations, moyamoya disease, or infectious aneurysms
5. Simultaneous treatment of two or more aneurysms
6. Already receiving antiplatelet agents, such as ticlopidine, clopidogrel, prasugrel, cilostazol, and aspirin
7. History of allergies to lactose, aspirin, or salicylate-based medications
8. Inability to undergo magnetic resonance imaging (MRI)
9. Contraindications to aspirin
10. Considered inappropriate for participation in the study by the treating physician

Randomization

Patients at each center will be allocated in a 1:1 ratio to either the aspirin or placebo groups using a dynamic allocation method (i.e., minimization) with a random element in the treatment assignment via an interactive web response system. Minimization will be performed with the following stratification factors: age (≥65 years, <65 years), sex (men, women), World Federation of Neurosurgical Societies (WFNS) grade (I–III, IV–V), and modified Fisher grade (0–2, 3–4) [8,9].

As this study is a double-blind trial, the investigators, study personnel involved in the treatment or clinical evaluation of the patients, and each patient will be unaware of the treatment administered to each patient throughout the study, except in cases of serious adverse events for which a causal relationship to the study treatment cannot be ruled out or when the investigator determines that unblinding is necessary to ensure the safety of the patient. The study coordinators, other than the investigators responsible for the intervention, prepare the test drug and create a correspondence table of the trial drugs, either aspirin or placebo, and their respective drug numbers. Each drug is stored in a bag that cannot be seen from outside. To ensure the quality of the study drug, it will be prepared and sent to each center approximately every 3 months while maintaining double-blinding.

Intervention

In this trial, the patients will receive EVT for RAs under general anesthesia within 72 h of onset. Administration of a specified number of drugs (aspirin 200 mg or lactose 200 mg) at the time of enrollment and allocation will be performed via the gastric tube by the physician in charge of anesthesia or the study co-investigator after the induction of general anesthesia, without revealing the contents of the medication to the operator group. This ensures the double-blind status of both the study participants and the investigators.

EVT for RAs will be performed under systemic heparinization, targeting an intraoperative activated clotting time of 250–300 s. Detachable coils will be placed in the aneurysm sac using a microcatheter to navigate the aneurysm. Treatment will be terminated when sufficient embolization is achieved. If the patient shows thrombus formation around the aneurysm neck or parent vessel or significant coil protrusion into the parent vessel requiring rescue stent placement, opening the emergency key to verify the medication details and administering additional antiplatelet agents may be considered.

MRI will be performed within 6–48 h after EVT, and assessment of ischemic lesions and concordant neurological dysfunction will be performed by the responsible and co-investigator physician (INV), in addition to assessment by an Independent Review Committee (IRC) separately, with the outcome of the IRC assessment serving as the primary outcome. Postoperatively, the comprehensive management agreed upon by the participating facilities will be carried out. The basic protocol will involve head computed tomography (CT) performed within 48 h after EVT and 14 ± 2 days after EVT. Imaging will be performed as appropriate during this period, and all cerebral ischemic events within 14 days after MRI and all hemorrhagic events within 14 days after enrollment will be evaluated. In the event of adverse events, including hemorrhagic complications, the best possible medical care will be provided. If a serious adverse event occurs that cannot be ruled out as being related to the study drug or procedure, it will be reported to the administrator of the implementing medical institution and subsequently to the Certified Review Board of Tokyo Medical and Dental University for further review and consideration. In addition, the mRS score 90 days after the onset of SAH will be assessed by the INV in the outpatient clinic on a face-to-face basis. If a patient cannot visit the hospital or is hospitalized in another hospital, evaluations will be conducted via telephone interviews.

Outcomes

Exploratory outcomes

1. Number and size of ischemic lesions in MRI-DWI evaluated by the IRC and INV
2. Incidence rate of cerebral hemorrhage along the tube tract for ventricular drainage on CT scans in the first 14 days after EVT

This outcome is defined as the proportion of patients showing cerebral hemorrhage along the tube tract for ventricular drainage on CT in the first 14 days after EVT.

Data monitoring body

Study monitoring will be managed by an ASTOP-independent Data Monitoring and Safety Committee (DMSC) and will be conducted twice a year to ensure that the study is being conducted safely and in accordance with the protocol and that the data are being accurately collected. The DMSC will assess the validity and credibility of the study. Monitoring will be based on electronic case report forms of completed data collected in the data center and will be centrally monitored by the data center, research secretariat, and research representative physicians. The data center will submit the prepared periodic monitoring reports to the research office and representative research physicians.

Sample size estimates

The primary outcomes of this study are the incidence rates of intraoperative thromboembolic morbidity and symptomatic ischemic lesions on MRI-DWI as assessed by the IRC. Rie et al. reported that the incidence rates of thromboembolic events during coil embolization for cerebral aneurysms were 8.8% in 159 patients who received intraoperative treatment with antiplatelet agents and 17.6% in 102 patients who did not receive intraoperative treatment with antiplatelet agents [5]. In addition, based on the findings obtained from MRI-DWI on the day after EVT, 27 patients who underwent coil embolization for RAs were evaluated for ischemic lesions at affiliated institutions, and the percentage of patients with lesions ≥15 mm was 14.8% (4 of 27 patients). Based on these data, the incidence rates of intraoperative thromboembolic complications in the placebo-treated group and symptomatic ischemic lesions on MRI-DWI are both assumed to be 15%. We also assume that aspirin treatment will improve both the incidence of intraoperative thromboembolic morbidity and the incidence of symptomatic ischemic lesions on MRI-DWI by 10% in comparison with the placebo-treated group (i.e., both incidence rates will be 5% in the aspirin-treated group). Under these assumptions, a sample size of 460 patients (230 patients in each group) will be required to achieve 90% power for each intergroup comparison of the primary outcomes using the Pearson’s chi-square test at a two-sided significance level of 0.025. Thus, the target sample size is 484 patients (242 in each group), with a dropout rate of approximately 5%.

Statistical analyses

All analyses of the efficacy outcomes will be performed using the modified intention-to-treat (mITT) population. The mITT population will include all randomized patients, excluding (1) patients who have never received any study treatment (aspirin or placebo), (2) patients who do not have any post-randomization data, and (3) patients who violate the well-defined and objectively determinable selection and exclusion criteria. For all efficacy analyses, patients in the mITT population will be analyzed according to treatment group assignment at the time of randomization, regardless of the actual treatment received. Adjustment for multiplicity will be undertaken for the primary and key secondary outcomes but not for the other outcomes. The analytical methods for each efficacy outcome are as follows:

1. Analysis of the primary outcomes
   The superiority of the efficacy of the aspirin-treated group over the placebo-treated group will be confirmed using the Cochran–Mantel–Haenszel (CMH) test stratified by age (≥65 years, <65 years), sex (men, women), WFNS grade (I–III, IV–V), and modified Fisher grade (0–2, 3–4). To adjust for multiplicity, the significance level in the comparison between groups for each primary outcome will be set at 2.5% for the two-sided test. The number and percentage of patients with an event related to the outcome will be calculated in each group, and the difference in the percentages between the two groups (aspirin and placebo groups) and its 97.5% confidence interval (CI) will be estimated.
2. Analysis of the key secondary outcomes
   The number and percentage of patients who experienced an event related to the outcome will be calculated for each group. The difference in the percentages between the groups (aspirin vs. placebo group) and its 95% CI will be estimated. If the upper limit of the 95% CI is <10%, the non-inferiority of the efficacy of the aspirin-treated group to the placebo-treated group will have been demonstrated. To adjust for multiplicity among the key secondary outcomes, the closed testing procedure will be used in the order of ranking: incidence of all bleeding events within 14 days of enrollment and incidence of cerebral ischemic events in the first 14 days after MRI.
3. Analysis of other secondary outcomes
   Group comparisons will be performed using CMH tests stratified by age (≥65 years, <65 years), sex (men, women), WFNS grade (I–III, IV–V), and modified Fisher grade (0–2, 3–4). The significance level will be set at 5% for two-sided tests. The number and percentage of patients with an event related to the outcome will be calculated for each group, and the difference in the percentage between the two groups (aspirin group vs. placebo group) and its 95% CI will be calculated. In addition, for the mRS score, the number and percentage of patients with mRS scores ranging from 0 to 6 points in the groups will be obtained, and the proportional odds model, including the treatment group as the independent variable, will be used to estimate the odds ratio and its 95% CI.
4. Analysis of exploratory endpoints
   The number and size of ischemic lesions on MRI-DWI will be summarized using the mean, median, standard deviation, minimum, maximum, Q1, and Q3 for each treatment group. For the incidence of cerebral hemorrhage along the tube tract in patients undergoing ventricular drainage on CT in the first 14 days after EVT, the number and percentage of patients with an event related to the outcome will be calculated in each group, and the difference in the percentages between the groups (aspirin vs. placebo group) and its 95% CI will be calculated.

Safety analysis will be performed on the safety analysis set, which is defined as the population that will be randomized and will receive the study treatment (aspirin or placebo). The data from the safety analysis set will be analyzed using the actual treatment received by the patient. Adverse event data will be listed individually and summarized by the number and percentage of patients in each treatment group in the safety analysis set. No interim analysis will be performed in this study.