Optimal Anti-Thrombotic Management Following Percutaneous Left Atrial Appendage Occlusion

• BACKGROUND:

Optimal antithrombotic therapy after percutaneous left atrial appendage occlusion (LAAO) to prevent device-related thrombosis (DRT) is not well established. The main aim of improving the drug strategy after appendage closure is to synergistically optimize the device-based thromboembolic (TE) prevention without increasing the risk of thrombus formation on device and bleeding events. Short-term dual antiplatelet therapy (DAPT) followed by long-term aspirin monotherapy is a strategy commonly prescribed after LAA occlusion. Nonetheless, a significant number of patients continues to suffer from major bleeding and device-related thrombosis (DRT). Recent data reported that, after percutaneous LAA occlusion, a significant activation of the coagulation system occurs, without evidence of a concomitant platelet activation [1]. However, OAC at full dose is not only contraindicated, but also potentially detrimental in patients with an indication for LAA occlusion, given their high bleeding risk and the resulting unsuitability to long term anticoagulation. Half-dose NOAC may provide improved protection against DRT and TE events, without increasing the risk of bleeding. The recent Assessment of Dual Antiplatelet Therapy Versus Rivaroxaban in AF Patients Treated with Left Atrial Appendage Closure (ADRIFT) study [2] reported a better control of thrombin generation in patients with half-dose rivaroxaban compared to DAPT. Additionally, in a prospective series of 555 AF patients, Della Rocca et al have documented long-term half-dose DOAC to be associated with significant reduction in the risk of the composite endpoint of DRT, TE and major bleeding events compared with a standard, antiplatelet based, antithrombotic therapy (2).

On the basis of these observations, we designed a randomized study to compare two antithrombotic regimens (long-term half-dose apixaban vs long-term aspirin after 45-days of full-dose apixaban) after successful Watchman implantation.

1.1 Safety Antithrombotic drugs, either with antiplatelet and anticoagulation therapy, is currently prescribed after Watchman implantation to prevent thrombus formation on device, which significantly increases the risk of stroke and peripheral thromboembolism. A possible side effect of antiplatelets (aspirin) and anticoagulants is excessive bleeding (hemorrhage), because these drugs increase the time it takes for blood clots to form.

The duration of the LAA occlusion procedure and of the related hospitalization will not be prolonged by this pilot study.

• STUDY RATIONALE Our primary hypothesis is that long-term half-dose apixaban would be superior to long-term aspirin for the primary endpoint. The 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
• 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.

• CRITERIA FOR EVALUATION 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
• 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
• 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.

7.5 Withdrawal of Subjects from the Study Reasonable attempts will be made by the investigator or staff to obtain a reason for subject withdrawals. The reason for the subject's withdrawal will be specified in the study database.

7.6 Replacement of Subjects Subjects who withdraw from the study will be replaced. 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

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.

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;
• Patient under legal protection.