Intracranial Hemorrhage Risk of Intensive Statin in Acute Ischemic Stroke With Cerebral Microbleeds

NCT ID: NCT05589454

Last Updated: 2022-10-21

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 344 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-01-31
• Study Completion Date: 2027-06-30

Brief Summary

This study is the first and largest secondary prevention trial about lipid-lowering therapy for acute ischemic stroke patients at high-risk of intracranial hemorrhage.

The primary hypothesis of this study is: excessive reduction in serum lipid levels by intensive statin therapy in acute ischemic stroke patients with cerebral microbleeds can increase the risk of intracranial hemorrhage.

This study will shed light on new clinical decisions regarding the long-term serum lipid management in these patients with dilemma in clinical practice.

Detailed Description

Cerebral microbleeds are an important subtype of cerebral small vessel diseases that have been established in approximately one third of patients with ischemic stroke and are associated with the risk of recurrent ischemic stroke, symptomatic intracranial hemorrhage, and all-cause death. In patients with ischemic stroke or transient ischemic attack, the relative and absolute risks of intracranial hemorrhage increase more rapidly than the risk of ischemic stroke with the increase of cerebral microbleeds burden, but the absolute incidence of ischemic stroke is still higher than that of cerebral hemorrhage.

It has been generally accepted that statins can effectively prevent recurrent ischemic stroke by reducing serum lipid levels. However, both low serum lipid levels and high dose of statins are clear risk factors for intracerebral hemorrhage, and the reduction of major serum lipid levels may increase the risk of cerebral microbleeds. Of note, the risk of statin mediated hemorrhage appears to depend on the degree of lipid reduction rather than statin use per se. These observations raise concerns about the safety of lipid-lowering therapy, especially intensive lipid-lowering therapy, in patients with acute ischemic stroke and cerebral microbleeds who are at high risk for future intracranial hemorrhage. It is still not clear that how to carry on the proper management of serum lipid levels in this particular population to reduce the recurrence of ischemic events as well as hemorrhagic events, for there is still a lack of clinical studies to explore the risk and benefit of different doses of statins to achieve different degrees of lipid regulation.

So, if it is proved that excessive reduction in serum lipid levels by intensive statin therapy in acute ischemic stroke patients with cerebral microbleeds can increase the risk of future intracranial hemorrhage, we will inform new clinical decisions regarding the long-term lipid management in these patients with dilemma in clinical practice.

Conditions

Acute Ischemic Stroke; Cerebral Microbleeds

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

High-dose atorvastatin

atorvastatin calcium tablets 80 mg, quaque nocte, continue to the end of the study

Group Type: EXPERIMENTAL

Atorvastatin Calcium tablets 80mg

Intervention Type: DRUG

Atorvastatin calcium tablets 4 pills (80 mg) will be given at a fixed time every night (24 ± 1 h between two doses) , orally, until the end of follow-up

Low-dose atorvastatin

atorvastatin calcium tablets 20 mg, quaque nocte, continue to the end of the study

Group Type: ACTIVE_COMPARATOR

Atorvastatin Calcium tablets 20mg

Intervention Type: DRUG

Atorvastatin calcium tablets 1 pill (20 mg) will be given at a fixed time every night (24 ± 1 h between two doses) , orally, until the end of follow-up

Interventions

Atorvastatin Calcium tablets 80mg

Atorvastatin calcium tablets 4 pills (80 mg) will be given at a fixed time every night (24 ± 1 h between two doses) , orally, until the end of follow-up

Intervention Type: DRUG

Atorvastatin Calcium tablets 20mg

Atorvastatin calcium tablets 1 pill (20 mg) will be given at a fixed time every night (24 ± 1 h between two doses) , orally, until the end of follow-up

Intervention Type: DRUG

Other Intervention Names

ALe produced by Jialin pharmaceutical company; ALe produced by Jialin pharmaceutical company

Eligibility Criteria

Inclusion Criteria

1. Patients with a non-cardioembolic ischemic stroke within 14 days prior to entry to the study

2. Adults between the ages of 18 and 85

3. Patients with cerebral microbleeds on baseline SWI imaging

4. Patients or their legal representatives volunteer to participate and sign written informed consent

Exclusion Criteria

1. Patients with severe acute ischemic stroke (NIHSS score ≥21)

2. Patients with coma (GCS score < 8)

3. Patients with previous moderate to severe dependence (mRS score 3-5)

4. Patients with any contraindications to CT and MRI (such as metal implants, claustrophobia, etc.)

5. Patients who are allergic to atorvastatin or excipients

6. Patients with intracranial hemorrhagic diseases confirmed by CT or MRI, such as cerebral hemorrhage, epidural hematoma, subdural hematoma, ventricular hemorrhage, subarachnoid hemorrhage, traumatic cerebral hemorrhage or hemorrhagic conversion of infarcts, etc

7. Patients within 6 months after hemorrhagic stroke

8. Patients with hemorrhagic tendency, such as abnormal coagulation function, Henoch-Schonlein purpura, platelet count less than 100×109/L or abnormal platelet function, etc

9. Patients who are ready to undergo or have undergone intravenous thrombolysis after the onset of the disease or who require urgent or recent (within 90 days) endovascular treatment;

10. Patients with severe hypertension (systolic blood pressure ≥ 185 mmHg or diastolic blood pressure ≥ 110 mmHg) that has not been controlled by treatment

11. Patients with hypoglycemia (< 2.7 mmol/L) or hyperglycemia (>22.2 mmol/L)

12. Patients with previous cerebral arteritis, brain tumor, cerebral parasitic disease, cerebral arteriovenous malformation, cerebral cavernous hemangioma, cerebral aneurysm, severe craniocerebral injury, or intracranial infection

13. Patients with previous severe valvular heart disease, atrial fibrillation, acute myocardial infarction or interventional therapy in the past 6 months, heart failure (patients classified as class III-IV according to the New York Heart Association [NYHA]) or patients with indications for pacemaker placement but without pacemaker installation or other malignant arrhythmias

14. Patients contraindicate to antiplatelet therapy;

15. Patients who must use other types of statins or other types of lipid-lowering drugs such as ezetimibe

16. Patients with severe mental disorders or dementia that are unable or unwilling to cooperate

17. Patients with active liver disease or unexplained 2 or more abnormal liver function tests (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥ 3.0× upper limit of normal [ULN])

18. Patients with myositis, myopathy, rhabdomyolysis, or 2 or more episodes of unexplained serum creatine kinase[CK] elevation ([CK]≥5.0×ULN)

19. Patients with other serious systemic or organic diseases that investigators believe will not allow evaluation of efficacy or are unlikely to complete the expected course of treatment and follow-up (e.g., malignancy, life expectancy < 3 years, etc.)

20. Women who are pregnant, breastfeeding or planning to become pregnant and who do not want to use contraception

21. Patients who participated in or are participating in other clinical trials during the 3 months prior to the study

22. Patients who are deemed ineligible for clinical trial participation by the investigator

23. Patients or their legal representatives do not consent to participate in this study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Science and Technology Department of Sichuan Province

OTHER

Sponsor Role: collaborator

Sichuan Provincial People's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Jialing Zhao

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jialing Zhao, MD

Role: PRINCIPAL_INVESTIGATOR

Departement of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital

Yang Xiang, MD

Role: STUDY_DIRECTOR

Departement of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital

Locations

Yunyang County People's Hospital

Chongqing, Chongqing Municipality, China

Chengdu Eighth People's Hospital

Chengdu, Sichuan, China

Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital

Chengdu, Sichuan, China

Ya 'an People's Hospital

Ya'an, Sichuan, China

Zigong Third People's Hospital

Zigong, Sichuan, China

Countries

China

Central Contacts

Jialing Zhao, MD

Role: CONTACT

jailynyy@163.com

+8618113137196

References

Zhao JL, Ai CB, Wang L, Yang SJ, Wang J, Yang W, Tang J, Zhang L, Li Y, Yan TQ, Gou S, Xie GG, Xiang Y. A multicenter, prospective, randomized controlled trial of intracranial hemorrhage risk of intensive statin therapy in patients with acute ischemic stroke combined with cerebral microbleeds (CHRISTMAS): Study protocol. Front Neurol. 2023 Feb 9;14:1097078. doi: 10.3389/fneur.2023.1097078. eCollection 2023.

Reference Type: DERIVED

PMID: 36846138 (View on PubMed)

Other Identifiers

zjl8803302022NSCSC1374

Identifier Type: -

Identifier Source: org_study_id