Effectiveness of Atorvastatin in Preventing Cerebrovascular Events After Flow Diverter Implantation

With the development of medical technology and materials and instruments, flow diverter (FD) has gradually become the most important treatment method for the treatment of intracranial aneurysms (IA). At present, FD has been used in more than 250,000 cases worldwide, and the overall 1-year complete occlusion rate of aneurysms can reach 75%-85.5%. However, although the current imaging prognosis of FD is encouraging, the perioperative complications of FD are as high as 12.9%, including ischemic complications, SAH, and parenchymal hemorrhage in 7.3%, 2.0%, and 2.0%, respectively. In addition, an in-stent stenosis of more than 50% within one year has been reported in 10.2 to 15.0% of patients. However, in addition to conventional dual antiplatelet therapy, there is no relevant guideline recommendation or clinical evidence on how to prevent complications after FD implantation in IA patients. Atorvastatin is widely used in the primary and secondary prevention of cardiovascular and cerebrovascular diseases. Its main effect is to improve the incidence of cardiovascular and cerebrovascular events by reducing blood lipids. However, there is no high-quality clinical evidence for the use of atorvastatin in intracranial aneurysm stent implantation. Previous retrospective studies have shown that atorvastatin is the only protective factor for in-stent restenosis after flow diverter implantation in intracranial aneurysms. Therefore, this study planned to conduct a randomized controlled clinical trial to confirm the efficacy and safety of oral atorvastatin in the prevention of cerebrovascular adverse events after stent implantation in patients with unruptured intracranial aneurysms, and to provide objective evidence for the treatment decision of patients with unruptured intracranial aneurysms to prevent cerebrovascular adverse events after flow diverter implantation.

1. Objectives of the study 1.1. Primary objective: To evaluate the efficacy of oral atorvastatin in preventing adverse cerebrovascular events within 1 year after flow diverter implantation in patients with intracranial aneurysms.

1.2. Secondary Objectives:

1. To evaluate the effectiveness of atorvastatin treatment in the prevention of adverse cerebrovascular events at 30 days and 180 days.
2. To evaluate the safety of atorvastatin treatment in patients with unruptured IA within 1 year after flow diverter implantation.
3. To evaluate the efficacy of atorvastatin in the prevention of in-stent stenosis events at 1 year after flow diverter implantation, and to explore its intervention effect on the degree of in-stent stenosis.

And (4) to evaluate whether there is a difference in the embolization rate of treated aneurysms between atorvastatin treatment and placebo at 1 year after flow diverter implantation.

2. Research hypothesis Atorvastatin treatment can effectively prevent cerebrovascular adverse events in patients with unruptured intracranial aneurysms treated with flow diverter implantation.

3. Study design This study was a multicenter, randomized, double-blind, placebo-controlled, superiority clinical trial to evaluate the efficacy and safety of oral atorvastatin in the prevention of postoperative cerebrovascular events in patients with unruptured intracranial aneurysms treated with flow diverters. Subjects press 1: Patients were followed up at postoperative day, discharge day, 30±3 days, 180±7 days, and 12±1 month. Neurological examination and mRS Scores were evaluated by observers at each follow-up period. According to the clinical symptoms and scores of the subjects, the observer decided whether to conduct further CT/CTA, MR/MRA, and DSA to confirm whether there were cerebrovascular events.

4. Study subjects Patients 18 to 75 years of age who had a diagnosed unruptured intracranial aneurysm and were intended to be treated with a flow diverter met all the inclusion criteria and none of the exclusion criteria. According to the PLUS study, the incidence of cerebrovascular events after the treatment of intracranial aneurysms with flow diverter device was 35.8%, which was used as the reference level. Combined with the retrospective analysis of our center, the incidence of cerebrovascular events was expected to be less than 13%, which was better than 10% of the control group. When the power was 80%, the sample size estimation formula for superiority design of qualitative variables was used, and the dropout rate was estimated to be 15%. 193 patients were required to be recruited in each group, and a total of 386 patients were enrolled in the two groups 4.1 Diagnostic Criteria Unruptured intracranial aneurysms were confirmed by CTA or MRA or DSA. 4.2 Inclusion Criteria

1. male or non-pregnant women aged 18-75 years;
2. Unruptured IA confirmed by CTA, MRA or DSA;
3. IA size ranged from 3 mm to 25mm;
4. Patients and/or their authorized persons can understand the purpose of the study, voluntarily participate in and sign informed consent;
5. patients who could be treated with flow diverter implantation according to the evaluation of the investigator;
6. patients who were willing to be followed up and evaluated according to the clinical research protocol.

4.3 Exclusion Criteria

1. Patients with contraindications to atorvastatin treatment or patients with oral allergy to atorvastatin;
2. female patients in preparation for pregnancy, pregnancy, or lactation.
3. patients with other cardiovascular and cerebrovascular diseases except intracranial aneurysms.
4. patients with long-term oral atorvastatin therapy before surgery (continuous use of atorvastatin for more than 1 month).
5. patients with ruptured IA or patients with previous surgical treatment for IA.
6. taking transport protein inhibitors, cyclosporine, protease inhibitors, other lipid-lowering products (fibrates, ezetimibe, evolocumab), antacids, erythromycin, cytochrome P450 enzymes, colchicine and other concomitant drugs that interact with atorvastatin metabolism.
7. patients with multiple intracranial aneurysms requiring treatment of ≥2 intracranial aneurysms within 1 year;
8. patients with blood blister-like aneurysm, fusiform aneurysm, dissecting aneurysm, pseudoaneurysm, infectious aneurysm, arteriovenous malformation related aneurysm, moyamoya disease related aneurysm.
9. known severe allergy to contrast media or to anticoagulant, antiplatelet drugs, anesthetic drugs, Nitinol alloy Patients with established allergies or contraindications.
10. patients who were not suitable for intravenous anesthesia or tracheal intubation general anesthesia according to the evaluation of anesthesiologists.
11. patients who did not understand or were unwilling to undergo follow-up evaluation as required by the clinical research protocol.
12. life expectancy \<3 years.
13. patients who were participating in clinical trials of other drugs or medical devices.

5.Blind method The trial drug "atorvastatin calcium tablets 20mg" was white oval film coated tablets, tasteless. In the control group, "starch mimic tablet 20mg" was used as a white oval film coated tablet. The outer packaging of the drug was aluminum blister eye packaging.

In order to ensure the blinding of the investigators and subjects during the execution of the trial, the unblinded personnel responsible for the administration and configuration of the trial drug will sign a confidentiality agreement. The investigators, other blinded investigators, subjects, and the sponsor will not have access to any information about the group assignment and related documents of the trial drug.

6.Endpoints

Primary outcome measures:

6.1Efficacy endpoint: no new cerebrovascular adverse events within 1 year.

Including new cases caused by various reasons:

① hemorrhagic stroke; (New cerebral hemorrhage confirmed by head CT)

② ischemic stroke; (Neurological impairment more than 24 hours after onset or new acute cerebral infarction lesion confirmed by imaging)

③ Angiographic follow-up at 12±1 month, degree of in-stent stenosis ≥50% (measured by WASID method)

Secondary end points:

6.2 Safety endpoint: no new moderate or serious adverse events within 1 year.

Meet one of the following conditions:

① Muscle-related adverse events (sports, trauma and other injuries were excluded); ② new-onset diabetes; ③ Dyspepsia or abdominal pain (unexplained for other reasons); ④ gallbladder-related adverse events; ⑤ Heavy bleeding. ⑥ all other patients who met the definition of moderate or serious adverse events. ⑦ Diagnosis of new cancers; (8) new-onset neurocognitive disorders; ⑨ Cataract.

1. All-cause mortality events (within 1 year)
2. Incident ischemic stroke events (within 1 year)
3. New hemorrhagic stroke events (within 1 year)
4. New stent thrombosis events (within 1 year)
5. New symptomatic stenosis events (within 1 year)
6. In-stent stenosis (stenosis ≥50% by WASID method) occurred at the 12th ±1 month of angiographic follow-up.
7. Degree of in-stent stenosis (as measured by WASID method) at the 12th ±1 month annual angiographic follow-up Target aneurysm embolization rate at 12±1 month annual angiographic follow-up (Raymond and OKM classification)

Eligibility Criteria:
Inclusion Criteria:

1. male or non-pregnant women aged 18-75 years;
2. IA confirmed by CTA, MRA or DSA;
3. IA size ranged from 3 mm to 25mm;
4. Patients and/or their authorized persons can understand the purpose of the study, voluntarily participate in and sign informed consent;
5. patients who were considered by the investigators to be suitable for stent treatment;
6. patients who were willing to be followed up and evaluated according to the clinical research protocol.

Exclusion Criteria:

1. Patients with contraindications to atorvastatin treatment or patients sensitive to atorvastatin; "Female patients who are preparing for pregnancy, pregnant, or lactating."
2. patients with intracranial aneurysm (excluding other cardiovascular and cerebrovascular diseases).
3. patients with indications for atorvastatin treatment (according to the Chinese Guidelines for Lipid Management (2023)).
4. patients with ruptured aneurysms.
5. taking transport protein inhibitors, cyclosporine, protease inhibitors, other lipid-lowering products (fibrates, ezetimibe, evolocumab), antacids, erythromycin, cytochrome P450 enzymes, colchicine and other concomitant drugs that interact with atorvastatin metabolism.
6. patients who did not understand or were unwilling to follow up and evaluate according to the clinical research protocol.
7. life expectancy \<3 years.