Evaluation of Edoxaban, Apixaban, and Dabigatran Versus Vitamin K Antagonists in Post-Cardiac Surgery Patients with Atrial Fibrillation Requiring Anticoagulation

The primary objective of the Direct Oral Anticoagulation versus Vitamin K Antagonist after Cardiac Surgery (DANCE) Trial is to evaluate the **safety** of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKAs) in patients with **atrial fibrillation** (AF) who require anticoagulation following cardiac surgery. This assessment is crucial as it addresses the need for effective and safe anticoagulation management in this patient population, potentially influencing clinical practice by providing evidence on the comparative safety profiles of these anticoagulant therapies. The trial aims to determine the feasibility of conducting a large randomized controlled trial (RCT) to further explore these safety outcomes.

The clinical trial involves a total of **5215 participants** diagnosed with **atrial fibrillation** requiring anticoagulation. The study population includes both male and female subjects, aged 18 years and older, who have undergone open heart surgery within the last 10 days. Participants were selected based on their medical condition and the requirement for oral anticoagulation therapy, either due to pre-existing or post-operative atrial fibrillation. The trial includes a vulnerable population, and informed consent was obtained from either the patient or a substitute decision-maker. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants are representative of the broader population affected by atrial fibrillation requiring anticoagulation post-cardiac surgery.

The clinical trial is designed to evaluate the safety and efficacy of **direct oral anticoagulants** (DOACs) compared to **vitamin K antagonists** (VKAs) in patients with **atrial fibrillation** requiring anticoagulation following cardiac surgery. This is a Phase III, randomized, double-blind, controlled trial. The trial is authorized to commence on October 25, 2024, with an estimated completion date of July 31, 2027. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), recent open heart surgery, and the requirement for anticoagulation. Informed consent is mandatory for participation.

Participants will be randomly assigned to receive either a DOAC or a VKA, with the treatment period lasting up to 90 days. The primary endpoint is the incidence of major bleeding at 30 days, while secondary endpoints include a composite of stroke and non-central nervous system systemic arterial embolism at 30 and 90 days, as well as other safety and efficacy measures. Follow-up visits will be scheduled at 30 and 90 days to assess these endpoints, with additional assessments for quality of life and patient satisfaction using validated questionnaires.

The expected length of participant involvement is approximately 6 months, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide high-quality evidence on the comparative safety and efficacy of DOACs versus VKAs in this patient population.

The clinical trial involves the administration of several **anticoagulant** medications, each with specific dosing regimens and administration routes. **Edoxaban** is provided in the form of a film-coated tablet, with a maximum daily dose of 60 mg. It is administered orally, and the treatment period extends up to 90 days. Compliance with the dosing schedule is monitored throughout the trial.

**Apixaban** is also administered as a film-coated tablet, with a maximum daily dose of 10 mg. The route of administration is oral, and the treatment duration is set for 90 days. Participant adherence to the dosing regimen is closely observed.

**Dabigatran** is provided in a hard capsule form, with a maximum daily dose of 300 mg. It is administered orally, and the treatment period is 90 days. Monitoring of participant compliance is conducted to ensure adherence to the prescribed dosing schedule.

**Phenprocoumon** is administered in tablet form, with a maximum daily dose of 40 mg. The route of administration is oral, and the treatment duration is 90 days. Compliance with the dosing regimen is monitored throughout the trial.

**Warfarin** is provided in tablet form, with a maximum daily dose of 10 mg. It is administered orally, and the treatment period extends up to 90 days. Participant adherence to the dosing schedule is closely monitored.

**Rivaroxaban** is administered as a film-coated tablet, with a maximum daily dose of 20 mg. The route of administration is oral, and the treatment duration is 90 days. Compliance with the dosing regimen is observed to ensure participant adherence.

All medications are administered orally, and the trial ensures that participant compliance with the dosing schedules is monitored to maintain the integrity of the study. The trial does not include any non-experimental treatments such as placebo or comparator treatments. Each medication is used in its standard pharmaceutical form, and no pediatric formulations are involved in this study. The trial is conducted under authorized conditions, with all medications having a product authorization status of 2, indicating their approval for use in the trial.

The efficacy of the clinical trial titled "The Direct Oral Anticoagulation versus Vitamin K Antagonist after Cardiac Surgery (DANCE) Trial" will be assessed using a series of primary and secondary endpoints. The primary endpoint is the incidence of major bleeding at 30 days, defined as bleeding that results in death, symptomatic bleeding in a critical area or organ, bleeding into a surgical site requiring reoperation, bleeding leading to hospitalization, or bleeding that causes a drop in hemoglobin level of 20g/L or more, or requires the transfusion of two or more units of packed red blood cells or whole blood.

Secondary endpoints include a composite of stroke and non-central nervous system systemic arterial embolism at 30 and 90 days, major bleeding at 90 days, pleural effusion requiring drainage, pericardial effusion requiring drainage, systemic arterial embolism, ischemic stroke, deep vein thrombosis, pulmonary embolism, all-cause mortality, and length of postoperative hospital stay at 30 and 90 days. Additionally, all-cause mortality at 6 months, minor bleeding, all bleeding, myocardial infarction, valve thrombosis, hemorrhagic stroke, all stroke, all arterial thrombosis/thromboembolism, quality of life measured by the EQ-5D-5L questionnaire, patient satisfaction with their anticoagulant treatment as assessed by the Perception of Anticoagulant Treatment Questionnaire (PACT-Q), and aggregate costs for both groups at 30 and 90 days will be evaluated.