A EUROpean Randomized Study on Blood-thinners and Cholesterol-lowering Treatments to Prevent Future Vascular Events in People With Covert Brain Infarcts (CBI)

MACCE are defined as the occurrence of any of the following events

• All cause death: Death from any cause
• Acute myocardial infarction: Admission with a discharge diagnosis of ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) and
• Stroke: AIS* or Intracerebral hemorrhage (non-traumatic) *Including Transient Ischemic Attack (TIA) with evidence of brain tissue infarction i.e. remission of symptoms within 24 hours but who have an acute ischemic lesion on diffusion weighted imaging MRI.

All events qualifying for a MACCE event will be adjudicated by the Clinical event committee.

Accepted timeframe for evaluation is +/- 30 days

Major and fatal bleeding events are defined according to criteria established by the International Society on Thrombosis and Haemostasis (ISTH):

• Fatal bleeding, and/or
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or
• Bleeding leading to a drop in hemoglobin of ≥20 g/L (1.24 mmol/L), or requiring transfusion of two or more units of whole blood or red cells.

All qualifying events will be adjudicated by an independent Clinical Event Committee (CEC).

The accepted time window for assessment is ±30 days.

Dementia is identified through phone contact and review of the patient's electronic health record, based on national diagnostic standards. Accepted diagnoses align with ICD-10 and ICD-11. ICD-10 codes include: dementia in Alzheimer's disease (F00.0-F00.9, DG30.0-DG30.9), vascular dementia (F01.0-F01.9, F00.2), dementia in other diseases classified elsewhere (F02.0-F02.8), unspecified dementia (F03.9), Lewy body dementia (DG31.8E), progressive isolated aphasia (DG31.0A), Pick disease (DG31.0B), and unspecified degenerative disease of the nervous system (DG31.9). ICD-11 codes include: dementia due to Alzheimer's disease (6D80), cerebrovascular disease (6D81), Lewy body disease (6D82), frontotemporal dementia (6D83), other specified diseases (6D85.Y), and dementia of unknown or unspecified cause (6D8Z). The accepted time window for evaluation is ±30 days.

Information about cardiovascular mortality is collected from telephone contacts and from the patient's electronic health record. See the table below for the definition of cardiovascular mortality.

Cardiovascular Mortality are defined as:

• Acute MI
• Sudden cardiac death
• Heart failure
• Stroke: death as a direct consequence or complication of stroke
• Cardiovascular procedure
• Cardiovascular-related haemorrhage: non-stroke intracranial haemorrhage (subdural hematoma), non-procedural or non-traumatic vascular rupture (e.g. aortic aneurysm), or haemorrhage causing cardiac tamponade
• Death due to other cardiovascular causes: a cardiovascular death not included in the above categories but with a specific, known cause (e.g., pulmonary embolism or peripheral arterial disease)

Accepted time for evaluation is +/- 30 days

A significant cognitive decline, defined as a ≥2-point reduction in Montreal Cognitive Assessment (MoCA) scores at 36 months.

The participant's score on the full 12 item in-person MoCA (30 points) at the initial visit is compared to the scores on the telephone administrated Tele-MoCA (items from MoCA not requiring the use of a pencil and paper or visual stimulus, maximum of 22 points) after 12 and 36 months.

Accepted time for evaluation is +/- 30 days

Information on SAEs will be reported by the investigators and recorded in the eCRF.

Simple SVD defined as score: Microbleeds: 0 microbleeds = 0 point; ≥ 1 microbleed = 1 point White matter hyperintensities (Fazekas): Fazekas 0-1 = 0 point; Fazekas 2-3 = 1 point. Lacunes: 0-2 lacunes = 0 point; >2 lacunes = 1 point. Total SVD score (range): 0-3.

Baseline physical activity levels are measured by the International Physical Activity Questionnaire (IPAQ).It yields a categorical score: low, moderate, or high level of physical activity. The follow-up assessment will be performed by staff from the enrolling site.

Accepted time for evaluation is +/- 30 days

The change in mRS score will be assessed to evaluate shifts in functional independence and disability over time. The mRS ranges from 0 to 6, with higher scores indicating worse outcomes. The follow-up assessment at 12 and 36 months will be performed by staff from the enrolling site.

Accepted time for evaluation is +/- 30 days

The change in CFS score will be assessed from baseline to 12 and 36 months to evaluate the progression of frailty and its impact on functional status and overall health over time. It ranges from 1 to 9, with 1 indicating "very fit" and 9 indicating "terminally ill." The follow-up assessments at 12 and 36 months will be performed by staff from the enrolling site Accepted time for evaluation is +/- 30 days

The Barthel Index is a score that describes the degree of independence in relation to assistance from another person. It ranges from 0 to 100, with higher scores indicating greater independence. A score close to 100 reflects that the individual is self-sufficient, whereas lower scores indicate increasing dependence on others in daily activities. A score near 0 typically suggests that the individual is bedridden and requires help with all tasks.

The follow-up assessments at 12 and 36 months will be performed by staff from the enrolling site.

Accepted time for evaluation is +/- 30 days

The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.

The follow-up assessments at 12 and 36 months will be performed by staff from the enrolling site.

Accepted time for evaluation is +/- 30 days

The CBI subtype and infarct appearance will be described by the enrolling physician, who has been trained to identify these findings on MRI.

The baseline MRI will be visually graded by the investigators and the total SVD score calculated.

The DICOM (Digital Imaging and Communications in Medicine) file containing the MRI will be downloaded and uploaded to the electronic case report form (eCRF) at redcap.au.dk, for later assessment by an imaging core lab.

At centers participating in the extended imaging sub-study, patients will be invited to a follow-up MRI after 3 years (+/- 1 months). The baseline MRI should be of sufficient quality and with a field strength of 3 Tesla. The follow-up MRI will contain diffusion-weighted imaging, apparent diffusion coefficient, Susceptibility Weighted Imaging (preferred) or T2* gradient-recalled echo, and T2 fluid-attenuated inverse recovery. Newly developed lacunar and/or cortical infarctions will be recorded and a SVD score will be calculated. If possible T1 weighted sequences will be performed. The MRI will be uploaded to eCRF.

The number of CBIs, number of cerebral microbleeds, deep white matter lesions (Fazekas grade), MRI SVD score, and Global Cortical Atrophy (GCA) Scale will be assessed by two blinded assessors. If there is disagreement, a third and final blinded assessor will perform the assessment.

WML volume will be estimated using semiautomatic software, such as 3D Slicer (an open-source medical image analysis tool) or a similar alternative. WML will be segmented together with volume quantification. It will be performed by two blinded assessors, and the final volume will represent a consensus volume between the assessors.

At centers participating in the extended imaging sub-study, patients will be invited to an ultrasound examination at the baseline visit. The common- and internal carotid artery will be assessed for signs of atherosclerotic disease and presence, size and morphology of plaques, classifying them based on echogenicity (homogeneous or heterogeneous), surface characteristics (smooth or irregular), and calcification (presence or absence) ipsilateral to the CBI. If bilateral CBIs are present, the left side will be scanned.

A plaque score will be calculated based on sum scores for each plaque identified in the carotid and intracranial arteries based on size and morphology. Plaque Grading Consensus will be used and range from no plaque (IMT < 1.5mm), protuberant/diffuse < 1.5mm IMT, protuberant/ diffuse with IMT 1.5-2.4mm or protuberant/ diffuse with IMT >2.5mm.

Pulsatility Index (PI) of the mid- and distal middle cerebral artery (MCA) will be measured using transcranial Doppler ultrasound to assess blood flow resistance within cerebral vessels. It will be calculated based on the difference between peak systolic and end-diastolic blood flow velocities relative to the mean flow velocity:

PI=(Peak Systolic Velocity-End-Diastolic Velocity)/Mean Velocity. PI has been associated with increased microvascular resistance, white matter disintegration, plaque burden.