Optimal Anti-Thrombotic Management Following Percutaneous Left Atrial Appendage Occlusion (INTEGRAL)

STUDY RATIONALE The primary hypothesis is that long-term half-dose apixaban would be superior to long-term aspirin for the primary endpoint. Primary analysis will be performed on an intention-to-treat (ITT) basis. A post-hoc secondary analysis will also be performed.

STUDY OBJECTIVES Composite Primary Endpoint The primary endpoint will be a composite of device-related thrombosis (DRT), thromboembolic events [stroke/transient ischemic attacks (TIA)] and major bleeding events

4. STUDY DESIGN Study Overview Patients will be randomly assigned to long-term half-dose apixaban or long-term aspirin in a 1:1 ratio via a computer-generated system and using block sizes of 16 to 20 patients.

Patients randomized to long-term half-dose apixaban (Group hdNOAC) will receive half-dose (2.5mg BID) apixaban monotherapy throughout the study period.

Patients randomized to long-term aspirin (Group ASA) will receive full-dose (5mg BID) apixaban for 45 days followed by aspirin 81-100mg monotherapy throughout the study period.

For both groups, outpatient follow-up will occur at 3, 6, 9, 12 months and every 6 months thereafter. Routine TEE imaging will be scheduled at 2-3 and 6-9 months to assess device stability, presence of peri-device leak and thrombus formation on device.

The minimum follow-up for the last enrolled patients will be 9 months. There will be no extra costs associated to the procedure.

6. SUBJECT SELECTION 6.1 Study Population Consecutive patients undergoing LAA occlusion with a Watchman FLX device. 6.2 Inclusion Criteria

• Men and women ≥18 years of age;
• Patients who underwent a clinically successful LAA closure procedure with a Watchman device (device implanted without procedural or bleeding complication) within a day or are scheduled to undergo the LAAO procedure.
• Paroxysmal, persistent, or permanent AF patients irrespective of prior antithrombotic treatment are eligible for randomization,
• Written informed consent obtained from subject and ability for subject to comply with the requirements of the study.

6.3 Exclusion Criteria:

• Two or more clinical characteristics at baseline (age≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL) requiring apixaban dosage adjustment;

• Mechanical heart valves or valvular disease requiring surgery or interventional procedure;

• Mandatory indication for dual antiplatelet therapy (e.g. recent stent) or single anti-platelet treatment (SAPT) (e.g. high coronary risk);

• Any contra-indication or known allergy to aspirin or clopidogrel or apixaban;

• Any mandatory indication for anticoagulation for a reason other than AF (e.g. Pulmonary embolism);

• Ongoing major bleeding or complicated or recent (<72hours) major surgery;

• Recent myocardial infarction (<6 weeks);

• Recent TE event (<6 weeks)

• Recent Intracranial bleeding (< 6 months);

• Prasugrel or ticagrelor concomitant use

• Participating in an investigational drug or another device trial within the previous 30 days;

• High likelihood of being unavailable for follow-up or psycho-social condition making study participation impractical;

• Pregnancy or within 48 hours post-partum or breast-feeding women;

• Patients under legal protection

  7. STUDY PROCEDURES AND GUIDELINES All eligible patients will be contacted for enrollment. Prior to conducting any study-related activities, written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization forms will be signed and dated by the subject. At this time, the whole study protocol (drug therapy schemes and follow-up schedule) will be explained. Subjects will be consented in one of the dedicated rooms for pre-procedure preparation in the electrophysiology laboratory.

7.1 Baseline Assessment Demographic information (age, gender and relevant medical history) will be collected using a case report form for patients attending our hospitals.

7.2 Watchman FLX Implantation Procedure The patient will be brought to the electrophysiology laboratory in a fasting state. The LAA occlusion procedure will be performed under general anesthesia. The workflow for Watchman FLX implantation will remain the same, irrespective of the participation in the study.

7.3 Follow-up After the procedure, the patient will stay overnight in the hospital, as per standard hospital protocol after LAAO procedure that includes occlusion of the LAA using the Watchman device. The day after the procedure the patient will be prescribed one of the two pharmacological protocols (full-dose apixaban +aspirin vs half-dose apixaban therapy) based on the results of randomization. Follow-up will include transesophageal echocardiography (TEE) and trans-telephonic and/or in-person visits. As per standard protocol after Watchman FLX implantation, TEE will be scheduled at 2-3 months and, eventually, 6-9 months. Additionally, the patient will be contacted by our team of nurses or asked to attend in-person visits, if needed, to assess any possible side effects or discomforts associated with the procedure and eventually optimize the medical treatment.

7.4 Discontinuation of Subjects A subject may be discontinued from the study at any time. The following is a list of possible reasons for study treatment discontinuation: subject withdrawal of consent; investigators request for early termination of study.

Sample size Based on a recently published trial by our group (2), we estimate that there will be approximately 8.5% minimum absolute difference in the primary outcome between the abstinence and no abstinence group.

We estimate that a minimum of 107 patients per group will be necessary to provide 80% power at a 2-sided alpha level of 0.05.

By adjusting for an attrition rate of 10%, the adjusted total sample size required would be 234 patients (117 patients per group).

An interim analysis will be conducted after 50% enrollment is complete or after 2 years of enrollment, whichever comes first