Evaluation of Statin Therapy on Major Adverse Cardiovascular Events in Frail Elderly Patients with Recent Ischemic Stroke or Transient Ischemic Attack

The primary objective of this study is to evaluate the effect of initiating **statin therapy** versus no statin therapy on Major Adverse Cardiovascular Events (MACE)-free survival and health-related quality of life (HRQoL) over a two-year follow-up in frail individuals aged 70 and above with a recent **ischemic stroke** or **transient ischemic attack**. This is clinically relevant as it aims to determine the potential benefits of statin therapy in reducing cardiovascular events and improving quality of life in a vulnerable population, which could inform treatment guidelines and patient management strategies.

Secondary objectives include assessing the impact of statin therapy on cognitive functioning, frailty progression, functional outcomes, and societal costs. These objectives are important for understanding the broader implications of statin use beyond cardiovascular outcomes, potentially influencing healthcare policy and resource allocation.

The clinical trial involves participants who have experienced a **recent ischemic stroke or transient ischemic attack** (TIA) within six weeks prior to inclusion. The study population consists of frail individuals aged 70 years and above, with both male and female subjects included. Participants are characterized by a pre-event score of 4-7 and/or a post-event score of 6-7 on the validated Clinical Frailty Scale, indicating a level of frailty. Importantly, individuals were not using statin therapy at the time of the index event. The sponsor has not provided information regarding the total number of participants. The trial does not specifically target a vulnerable population, and no particular lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the effect of initiating **statin** therapy versus no statin therapy on Major Adverse Cardiovascular Events (MACE)-free survival and health-related quality of life (HRQoL) over a two-year follow-up in frail individuals aged 70 and above with a recent ischemic stroke or transient ischemic attack (TIA). This is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial will span approximately five years, with an estimated recruitment start date in October 2024 and an estimated end date in October 2029.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, recent ischemic stroke or TIA, frailty status, and absence of current statin therapy. Follow-up visits are scheduled at 3, 6, 12, 18, and 24 months, with additional follow-up at three years for those enrolled early in the recruitment phase. These visits will assess primary endpoints, including MACE-free survival and HRQoL, as well as secondary endpoints like the number of new major cardiovascular events, cognitive function, falls, frailty status, and functional outcomes.

The expected length of participant involvement is up to three years, depending on the timing of enrollment. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any situation where continued participation is deemed not in the participant's best interest by the study investigators. The trial is categorized as a Phase 3 study, focusing on confirming the therapeutic benefits and risks of statin therapy in a larger patient population to support clinical decision-making and potential guideline revisions.

The clinical trial involves the administration of several **statin** medications, each with specific pharmaceutical forms, dosages, and administration routes. The first experimental medication is **Fluvastatin**, marketed as Fluvastatine 20 mg PCH, capsules. This medication is provided in capsule form and is administered orally. The maximum daily dose is 80 mg, with a total maximum dose of 87,600 mg over a treatment period of up to 36 months. The active substance, fluvastatin, is of chemical origin and is manufactured by Pharmachemie BV.

Another medication used in the trial is **Simvastatin**, available as Simvastatine Mylan 40 mg, film-coated tablets. These tablets are also administered orally, with a maximum daily dose of 80 mg and a total maximum dose of 87,600 mg over a 36-month period. The active substance, simvastatin, is chemically derived and produced by Mylan Pharmaceuticals Limited.

**Pravastatin Sodium** is included in the trial under the name Pravastatine Viatris 10 mg Tabletten. This medication is provided in tablet form and administered orally. The dosing schedule allows for a maximum daily dose of 80 mg, with a total maximum dose of 87,600 mg over a 36-month treatment period. The active substance, pravastatin sodium, is of chemical origin and manufactured by Viatris GX.

**Atorvastatin** is administered as Atorvastatine Viatris 10 mg Filmtabletten, which are film-coated tablets taken orally. The maximum daily dose is 80 mg, with a total maximum dose of 87,600 mg over a 36-month period. The active substance, atorvastatin, is chemically derived and produced by Viatris GX.

Lastly, **Rosuvastatin** is used in the trial as Rosuvastatine Viatris 5 mg Filmtabletten. These film-coated tablets are administered orally, with a maximum daily dose of 80 mg and a total maximum dose of 87,600 mg over a 36-month treatment period. The active substance, rosuvastatin, is of chemical origin and manufactured by Viatris GX.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial aims to evaluate the effect of initiating statin therapy on major adverse cardiovascular events and health-related quality of life in frail individuals aged 70 and above with a recent ischemic stroke or transient ischemic attack.

Efficacy in the clinical trial titled "StAtins in Frail oldEr patients with ischemic Stroke or Transient ischemic attack – The Randomized Controlled Trial" will be assessed using both primary and secondary endpoints. The primary endpoints include **MACE-free survival** over a two-year period and Health-Related Quality of Life (HRQoL). MACE-free survival will be measured at 3, 6, 12, 18, and 24 months, with additional follow-up at three years for participants enrolled early in the recruitment phase. HRQoL will be evaluated using the Patient-Reported Outcomes Measurement Information System - Global-10 (PROMIS-10) at the same timepoints.

Secondary endpoints will assess the number of new major cardiovascular events, cognitive function at 12 and 24 months, falls (number and time to first fall), frailty status at 12 and 24 months, and functional outcomes at 12 and 24 months. These efficacy parameters will be collected and analyzed according to the trial's schedule to determine the impact of initiating statin therapy versus no statin therapy on the specified outcomes in frail individuals aged 70 and above with a recent ischemic stroke or transient ischemic attack (TIA).