Evaluation of Clopidogrel, Atorvastatin, Rosuvastatin, and Acetylsalicylic Acid in Covert Brain Infarction: A Multicenter Randomized Controlled Trial

The primary efficacy objective is to evaluate whether the addition of antiplatelet therapy and/or statins to standard risk factor management provides a long-term benefit in reducing major adverse cardiac and cerebral events (MACCE) and death at 3 years in patients with covert brain infarction. The primary safety objective is to assess the cumulative risk of major and fatal bleeding over 36 months. 5, 3, 4

Secondary objectives include the evaluation of several clinical outcomes at 36 months, including:

• Incidence of all-cause dementia and cognitive decline, specifically measured by reductions in Montreal Cognitive Assessment (MoCA) scores.
• Cumulative risk of cardiovascular-related mortality, all-cause mortality, stroke, and myocardial infarction.
• Incidence of serious adverse events (SAE).
• Stratified analysis of MACCE, dementia, and mortality based on systolic blood pressure, low-density lipoprotein (LDL) levels, high-sensitivity C-reactive protein (hs-CRP), small vessel disease (SVD) scores, lacunar versus cortical infarct subtypes, and physical activity levels.
• Changes in functional status, frailty, and functional independence as assessed by the Modified Rankin Scale (mRS), Clinical Frailty Scale (CFS), and Barthel Index (BI).
• Changes in quality of life using the EQ-5D instrument.
• Neuroimaging markers, including white matter lesion (WML) volume and SVD progression via MRI, as well as carotid plaque quantification and middle cerebral artery pulsatility index via ultrasound.
• Long-term follow-up of MACCE, mortality, and dementia at 5 and 10 years.

This clinical trial involves 100 patients, including both males and females, aged between 50 and 74 years. The study population consists of individuals diagnosed with covert brain infarction, characterized by deep/lacunar or cortical infarcts identified via magnetic resonance imaging without prior symptoms of transient ischemic attack or stroke. Eligible participants must have a life expectancy exceeding 12 months and maintain a level of independence in activities of daily living, defined by a modified Rankin Scale score of 3 or less. The primary objectives are to evaluate the long-term benefit of antiplatelet therapy and/or statins in reducing major adverse cardiac and cerebral events and to assess the cumulative risk of major and fatal bleeding over a 36-month period.

This phase III, multicenter, randomized trial evaluates the efficacy and safety of antiplatelet and/or statin therapies in patients with covert brain infarction. The study aims to determine if the administration of clopidogrel, acetylsalicylic acid, atorvastatin, or rosuvastatin, in addition to risk factor management, reduces the incidence of major adverse cardiac and cerebral events (MACCE) over a 3-year period. The primary safety objective is to assess the cumulative risk of fatal or major bleeding during the 36-month observation period. The research methodology includes a screening process to identify eligible participants based on MRI findings of lacunar or cortical infarcts, age, and functional independence. Study involvement extends for 3 years, with assessments conducted at baseline, 12 months, and 36 months to monitor functional independence, cognitive decline, and mortality. Secondary endpoints include evaluations of dementia, frailty, and small vessel disease markers. The trial follows a pragmatic design to observe therapeutic use in a clinical setting.

The experimental treatment includes clopidogrel administered via the oral route at a dosage of 75 mg.

The experimental treatment includes atorvastatin administered via the oral route at a dosage of 40 mg.

The experimental treatment includes rosuvastatin administered via the oral route at a dosage of 20 mg.

The experimental treatment includes acetylsalicylic acid administered via the oral route at a dosage of 100 mg.

The primary efficacy assessment is the incidence of Major Adverse Cardiac and Cerebral Events (MACCE) evaluated over a 3-year period in patients with covert brain infarction. Secondary efficacy parameters include cardiovascular mortality and dementia based on ICD-10 or ICD-11 diagnoses. Cognitive decline is measured using the MoCA-score, while biomarkers of inflammation, specifically Hs-CRP, are analyzed at baseline to determine correlations with future vascular events, mortality, and dementia. Physical activity levels are assessed at baseline via the International Physical Activity Questionnaire (IPAQ) to evaluate associations with MACCE at 36 months.

Functional status and health-related quality of life are evaluated through several longitudinal assessments at baseline, 12 months, and 36 months:

• Changes in the mRS score to evaluate shifts in functional independence and disability.
• Changes in the Clinical Frailty Scale (CFS) to monitor the progression of frailty.
• Changes in the Barthel Index (BI) to assess functional independence in daily activities.
• Changes in the EQ-5D score to measure variations in quality of life.

Neuroimaging and vascular assessments are also performed. At baseline, the MRI SVD score is estimated to assess the risk of future events, mortality, and dementia. Follow-up MRI after 3 years is used to record newly developed lacunar infarction or cortical infarction, and to calculate the Global Cortical Atrophy (GCA) Scale, Fazekas grade, and the number of cerebral microbleeds. Additionally, a sub-study utilizes ultrasonography to assess the common and internal carotid artery for atherosclerotic disease and plaques quantification.