Evaluation of Anticoagulant Therapy Discontinuation in Atrial Fibrillation Patients Post-Surgical Left Atrial Appendage Closure: A Randomized Non-Inferiority Trial

The primary objective of the study is to investigate the risk of **stroke**, systemic embolisms, and major bleeding events with and without anticoagulant therapy in patients with **atrial fibrillation** who have previously undergone surgical left atrial appendage closure. This is clinically relevant as it aims to determine the safety and efficacy of discontinuing anticoagulant therapy in this patient population, potentially impacting treatment guidelines and patient management strategies.

Secondary objectives include:

• Investigating the mortality risk with and without anticoagulant therapy in patients with atrial fibrillation who have previously undergone surgical left atrial appendage closure.
• Assessing the success of surgical left atrial appendage closure in patients who have previously undergone cardiac surgery, including surgical LAA closure.
• Evaluating and comparing the procedural success of different techniques of surgical left atrial appendage closure.
• Evaluating and comparing health-related quality of life in relation to discontinuing anticoagulant therapy.

The clinical trial involves participants diagnosed with **atrial fibrillation**, focusing on individuals who have previously undergone surgical left atrial appendage closure. The study population includes both male and female subjects, aged 18 years and older, with no specific vulnerable populations selected. Participants were chosen based on their documented history of paroxysmal, persistent, or permanent atrial fibrillation or atrial flutter, as recorded in electronic patient records. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria required participants to have undergone any type of cardiac surgical procedure, including surgical left atrial appendage closure, between January 1st, 2010, and April 1st, 2023, as documented in the National Patient Register or the Western Danish Heart Registry. The study does not emphasize any particular lifestyle considerations such as diet or physical activity. Participants were required to provide informed consent to be included in the trial.

The clinical trial is designed to evaluate the risk of stroke, systemic embolisms, and major bleeding events in patients with **atrial fibrillation** who have undergone surgical closure of the left atrial appendage. This study is a randomized, non-inferiority trial with a double-blind, controlled design. The trial is expected to commence recruitment on September 1, 2023, and conclude by September 1, 2028, with a maximum treatment period of 48 months for each participant. The investigational medicinal products include **apixaban**, **rivaroxaban**, **warfarin sodium**, **edoxaban**, and **dabigatran**, all administered orally. These products are authorized and will be used in accordance with their marketing authorization, ensuring minimal additional risk to participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, a history of atrial fibrillation or atrial flutter, and previous cardiac surgery including left atrial appendage closure. Informed consent is required for participation. Follow-up visits will be scheduled to monitor the primary endpoint, which is a composite of stroke, peripheral embolisms, and major bleeding events. Secondary endpoints include ischemic and hemorrhagic strokes, systemic embolism, and various mortality and quality of life measures. The end-of-study visit will assess the overall outcomes and any adverse events experienced during the trial.

Participant involvement is expected to last up to 48 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is categorized as low-intervention, as the investigational products are used within their approved therapeutic indications, posing minimal additional risk compared to standard clinical practice. The trial's design and procedures are structured to ensure rigorous assessment of the safety and efficacy of discontinuing anticoagulant therapy in the specified patient population.

The clinical trial involves the administration of several **anticoagulant** medications to evaluate their efficacy and safety in patients with atrial fibrillation who have undergone surgical closure of the left atrial appendage. The experimental medications include **Apixaban**, **Rivaroxaban**, **Warfarin Sodium**, **Edoxaban**, and **Dabigatran**. Each medication is administered orally, with specific dosage and treatment regimens.

**Apixaban** is provided in the form of a film-coated tablet. The maximum daily dose is 10 mg, with a total maximum dose of 15,000 mg over a treatment period of up to 48 weeks. Apixaban functions as a direct factor Xa-inhibitor, which is a class of anticoagulants that prevent blood clots by inhibiting the activity of factor Xa.

**Rivaroxaban** is also administered as a film-coated tablet. The maximum daily dose for Rivaroxaban is 20 mg, with a total maximum dose of 30,000 mg over the same treatment period of 48 weeks. Similar to Apixaban, Rivaroxaban is a direct factor Xa-inhibitor, contributing to its anticoagulant effects.

**Warfarin Sodium** is provided in tablet form, with a maximum daily dose of 10 mg and a total maximum dose of 15,000 mg over 48 weeks. Warfarin Sodium acts as a vitamin-K antagonist, specifically a coumarine derivative, which works by reducing the synthesis of vitamin K-dependent clotting factors, thereby exerting its anticoagulant effect.

**Edoxaban** is administered as a film-coated tablet, with a maximum daily dose of 60 mg and a total maximum dose of 90,000 mg over the 48-week treatment period. Edoxaban is another direct factor Xa-inhibitor, similar to Apixaban and Rivaroxaban, and functions by inhibiting the activity of factor Xa to prevent clot formation.

**Dabigatran** is provided in the form of a hard capsule, with a maximum daily dose of 300 mg and a total maximum dose of 450,000 mg over the 48-week period. Dabigatran is a direct thrombin inhibitor, which prevents clot formation by directly inhibiting the activity of thrombin, a key enzyme in the coagulation process.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed treatment regimens. The trial aims to assess the risk of stroke, systemic embolisms, and major bleeding events associated with these anticoagulant therapies in the specified patient population.

The efficacy of the clinical trial titled "Anticoagulant therapy in patients with atrial fibrillation after surgical closure of the left atrial appendage: a randomized non-inferiority trial (The ATLAAC trial)" will be assessed using a composite primary endpoint. This endpoint includes the occurrence of **stroke**, peripheral embolisms, and major bleeding events. Secondary endpoints will further evaluate efficacy through various parameters such as ischemic stroke, hemorrhagic stroke, severity of stroke according to the Scandinavian Stroke Scale, transient ischemic attack, systemic embolism, all-cause stroke, all-cause mortality, cardiovascular mortality, all types of bleeding leading to hospital contact, blood transfusions, myocardial infarction, deep venous thrombosis, pulmonary embolism, length and volume of the residual stump of the left atrial appendage (LAA), presence of contrast leakage across the closure line, presence of thrombi in the LAA or the left atrium, and health-related quality of life scores.

The trial will involve the use of authorized medicinal products, including APIXABAN, RIVAROXABAN, WARFARIN SODIUM, EDOXABAN, and DABIGATRAN, which are administered orally. The maximum treatment period for these products is 48 weeks. The trial is categorized as low intervention, as the investigational medicinal products are authorized and used in accordance with their marketing authorization, posing minimal additional risk or burden to the subjects compared to normal clinical practice. The trial is expected to start recruitment on September 1, 2023, and is estimated to end on September 1, 2028.