Evaluation of Antithrombotic Strategies with Aspirin and Clopidogrel Post-Left Atrial Appendage Closure in Atrial Fibrillation Patients

The primary objective of this study is to evaluate the efficacy of two different **antithrombotic** strategies, specifically aspirin versus a combination of aspirin and clopidogrel, following left atrial appendage closure (LAAC). This will be assessed by comparing the occurrence of ischemic lesions on brain MRIs performed within 24 hours after the procedure and after a 3-month follow-up. The clinical relevance of this objective lies in optimizing post-procedural management to reduce the risk of ischemic events in patients with atrial fibrillation, thereby potentially improving patient outcomes and reducing the incidence of stroke.

Secondary objectives include assessing the impact of each therapeutic strategy over a 3-month period on the occurrence of: - Death - Symptomatic cerebral ischemic events - All symptomatic systemic thromboembolic events - Cerebral hemorrhagic events - Systemic hemorrhagic events - Deterioration of cognitive functions - Thrombus on prosthesis - Residual leakage and endothelialization

Additionally, the study aims to evaluate the impact of the prosthesis implantation procedure itself on the occurrence of cardiac complications related to the procedure, such as pericardial effusion. These secondary objectives are crucial for understanding the broader implications of the therapeutic strategies and procedural interventions on patient health and safety.

The clinical trial involves a study population comprising both **male** and **female** participants, aged 18 years and older, who have an indication for left atrial appendage closure (LAAC) as per CNEDiMTS guidelines. The total number of participants is not provided by the sponsor. Participants are required to have a definitive contraindication for anticoagulation, as determined by a multidisciplinary heart team, and must be registered under the social security system. The trial does not include a vulnerable population. Participants' general health status is not specified, and no specific lifestyle considerations such as diet or physical activity are mentioned. Key inclusion criteria include the provision of written informed consent and approval by a heart team consisting of interventional cardiologists, neurologists, and other physicians.

The clinical trial is designed to evaluate the efficacy of two different **antithrombotic** strategies following left atrial appendage closure (LAAC) in patients with **atrial fibrillation**. The trial employs a randomized, double-blind, controlled design to compare the occurrence of ischemic lesions on brain MRIs between two groups: one receiving aspirin alone and the other receiving a combination of aspirin and clopidogrel. The trial is set to run for a total duration of approximately 31 months, with an estimated recruitment start date of October 3, 2022, and an estimated end date of May 3, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), written informed consent, and heart team approval. Following the LAAC procedure, participants will have a baseline MRI within 24 hours (D0) to assess initial ischemic lesions. Subsequent follow-up visits will occur at Day 1 (D1) and Month 3 (M3), during which additional MRIs and systematic neurological examinations will be conducted to monitor for ischemic and hemorrhagic events, as well as to assess neurological deficits and cognitive function using the NIHSS and MoCA scales.

The expected length of participant involvement is approximately three months, corresponding to the maximum treatment period with the study medications, which include KARDEGIC 160 mg oral solution and Plavix 75 mg film-coated tablets. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with the treatment regimen, or withdrawal of consent by the participant. The primary endpoint of the trial is the number of ischemic lesions appearing on cerebral MRI scans between the initial and three-month follow-up assessments. Secondary endpoints include symptomatic ischemic cerebral events, systemic thromboembolic and bleeding events, and treatment compliance, among others.

The clinical trial involves the administration of **KARDEGIC 160 mg**, a **poudre pour solution buvable en sachet** (oral solution), containing the active substance **D,L-lysine acetylsalicylate**. This medication is provided in sachets, each containing 160 mg of the active ingredient. The route of administration is oral, with a maximum daily dose of 160 mg. The total maximum dose over the treatment period is 14,400 mg, with a treatment duration of up to 3 months. The product is manufactured by Sanofi Winthrop Industrie and is authorized for use in France. The medication is chemically derived and classified under the ATC code B01AC06, which corresponds to acetylsalicylic acid.

Additionally, the trial includes the use of **Plavix 75 mg film-coated tablets**, which contain the active substance **clopidogrel**. This medication is also administered orally, with a maximum daily dose of 75 mg and a total maximum dose of 6,750 mg over the treatment period. The treatment duration is similarly up to 3 months. Plavix is manufactured by Sanofi Winthrop Industrie and is authorized for use in the European Union. The active substance is chemically derived and classified under the ATC code B01AC04, which corresponds to clopidogrel.

Both medications are used in the trial to evaluate the efficacy of two different antithrombotic strategies following left atrial appendage closure. The study aims to compare the occurrence of ischemic lesions on brain MRIs performed within 24 hours after the procedure and after 3 months of follow-up. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

The efficacy of the antithrombotic strategies in the clinical trial will be assessed by evaluating the occurrence of ischemic lesions on brain MRIs. The primary endpoint is the number of ischemic lesions appearing on the diffusion sequences and/or FLAIR between cerebral MRI scans performed within 24 hours of the procedure and after 3 months of anti-thrombotic treatment. Secondary endpoints include symptomatic ischemic cerebral events, systemic thromboembolic events, cerebral hemorrhagic events, systemic bleeding events, and neurological deficits. These will be identified through MRI, systematic neurological examinations, and clinical evaluations at specified timepoints, including Day 1 (D1) and Month 3 (M3).

Additional assessments will include the use of the NIHSS (National Institute of Health Stroke Score) and the modified Rankin score to measure neurological deficits and their functional impact. Cognitive assessment will be conducted using the Montreal Cognitive Assessment (MoCA) scale at D1 and M3. The presence of thrombus on the prosthesis, residual leakage, and the degree of endothelialization will be evaluated by cardiac CT scan at 3 months. Treatment compliance will be assessed at M3 by comparing treatments taken with those prescribed, and this compliance will be correlated with thromboembolic and hemorrhagic events to determine the impact of the treatment strategy.