LAAO Versus NOAC in Patients With AF and PCI

Study Overview
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Brief Summary
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Atrial fibrillation (AF) coincides with coronary artery disease (CAD) shared common risk factors and pathophysiologic pathways. CAD affects approximately 25% of AF patient according to the trial Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), while in the Global Registry of Acute Coronary Events (GRACE) atrial fibrillation affected about 9% of patients with CAD. It is reported that approximately 5-8% of the patients who underwent PCI had concomitated atrial fibrillation. For AF patients who underwent PCI, both antiplatelet and antithrombotic medications are required for preventing stent thrombosis and ischemic stroke, leading to an increased risk of bleeding. Finding a safe and effective balance between the risk of ischaemic events and bleeding complications is challenged by the shared risk factors for either event such as advanced age, congestive heart failure, hypertension, diabetes, previous stroke, etc.. Previous pivotal trials have shown that in patients with atrial fibrillation and requiring antiplatelet treatment, a NOAC plus clopidogrel regimen was associated with a lower incidence of bleeding events as compared with a warfarin-based triple antithrombotic strategy. Therefore, the current expert opinions and consensus of North American Societies recommend a NOAC plus a P2Y12 inhibitor in patients with AF and PCI. However, the NOAC plus clopidogrel strategy still led to 16.8% of clinically significant bleeding (PIONEER AF-PCI). Consequently, the compliance of OAC/NOAC is commonly suboptimal among PCI patients who require an antithrombotic strategy for AF. Percutaneous left atrial appendage occlusion (LAAO) is a non-pharmacological strategy for stroke prevention in patients with AF. Both randomized data and registries have confirmed it can be an alternative to oral anticoagulation in patients with nonvalvular AF. Current guidelines recommend LAAO for patients with NVAF who have contraindications or are unsuitable for long-term OAC. Considering the unique high risk of AF patients with PCI, LAAO may be an attractive treatment option by obviating the need for combined oral anticoagulation and antiplatelet therapy. However, so far there is no data from neither randomized cohorts nor real-world registries showing if LAAO can be a safe and effective alternative strategy compared to VKA/NOAC for stroke prevention in AF patients who underwent PCI. The PROTECT AF and PREVAIL studies showed that the percutaneous LAAO was non-inferior to warfarin therapy, and the PRAGUE-17 trial showed non-inferior to direct oral anticoagulants, however, the small sample size of these trials limited further subgroup analyses of the PCI sub-population. In the NCDR registry, which is the largest cohort of LAAO up to now, 20.3% of the LAAO patients had a prior myocardial infarction. However, the proportion of stent implantation was not reported. Among previous trials, the proportion of patients with coronary artery disease ranged from 28.5% to 47.5%. The large number of AF patients with CAD warrant the optimal stroke prevention strategy to be assessed in this population. The primary goal of the proposed study is to investigate if the non-inferiority would be met for the LAAO when compared to NOACs in NVAF patients with PCI in terms of a composite endpoint of any death, any stroke, any myocardial infarction, systemic embolism at 12 months. In addition, the powered key secondary will also have 80% of power to show superiority for the LAAO when compared to NOACs in terms of BARC type 2, 3, or 5 bleeding events at 36 months.

Official Title
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Left Atrial Appendage Occlusion Versus Novel Oral Anti-coagulation in Patients With Atrial Fibrillation and Percutaneous Coronary Intervention: a Randomized, Multicentre, Open-label, Non-inferiority Trial

Conditions
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Atrial Fibrillation, Percutaneous Coronary Intervention

Intervention / Treatment
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* Device: The WATCHMAN/WATCHMAN FLX device
* Drug: Rivaroxaban + Clopidogre
* Drug: Aspirin + Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Successful PCI for unstable angina or CCS Non-valvular atrial ﬁbrillation Concomitant at least one of the following conditions: congestive heart failure, hypertension, ≥65yrs, diabetes, previous stroke, TIA or thromboembolism Eligible for long-term novel oral anti-coagulation (NOAC) therapy Able to understand and provide informed consent and comply with all study procedures/medications Exclusion Criteria: Patients who meet any of the following criteria will be disqualified from participation in the study: Clinical exclusion criteria: Under the age of 18 Unable to give informed consent or currently participating in another trial and not yet at its primary endpoint Patient is a woman who is pregnant or nursing (a pregnancy test must be performed within 7 days prior to the index procedure in women of child-bearing potential according to local practice) Concurrent medical condition with a life expectancy of less than 3 years Haemodynamical unstable Known contraindication to medications such as heparin, antiplatelet or anticoagulation drugs, or contrast PCI for ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI), or experienced a peri-procedural myocardial infarction (MI) caused by PCI Known contraindication to LAAO or LAAO is not required Comorbidities other than atrial ﬁbrillation that required long term use of anticoagulation (such as implanted a mechanical valve) The patient had or is planning to have any cardiac (excluding the current PCI procedure) or non-cardiac interventional or surgical procedure within 30 days prior to or 60 days after the WATCHMAN device implant (e.g., cardioversion, ablation, cataract surgery) Ongoing overt bleeding Previous stroke/TIA within 30 days of enrolment Symptomatic carotid artery disease Severe renal insufficiency (CrCl≤30ml/min) Imaging Exclusion Criteria: Left atrial appendage (LAA) thrombus High risk patent foramen ovale or atrial septal defect requiring invasive treatment Anatomical unsuitable for LAAO Rheumatic heart valve disease, mitral valve stenosis (valve area <1.5cm2)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Percutaneous left atrial appendage occlusion (LAAO)<br>Device: The WATCHMAN/WATCHMAN FLX device Drug: Rivaroxaban 15 mg QD + Clopidogrel 75mg QD for 45 days, followed by Aspirin 100mg QD + Clopidogrel 75mg QD for 10.5 months after LAAO | Device: The WATCHMAN/WATCHMAN FLX device<br>* Watchman device was an umbrella-shaped, self-expanding, nitinol structure with a porous partial polyethylene terephthalate membrane (160 um mesh) and 10 struts. The membrane portion of the structure faces into the body of the left atrial to block embolization of thrombus and provide scaffolding on which endothelialization can occur. The On July 21st, 2020, the FDA approved the next generation LAAO device, named Watchman FLX. This newiteration of the Watchman LAAO platform offers full capability of recapture and redeployment of the device, decreasedmetallic exposure, an increased number of contact points for sealing, a fully rounded delivery shape, and precision anchors designed to provide optimal device engagement with the LAA.<br>Drug: Rivaroxaban + Clopidogre<br>* Previous pivotal trials have shown that in patients with atrial fibrillation and requiring antiplatelet treatment, a NOAC plus clopidogrel regimen was associated with a lower incidence of bleeding events as compared with a warfarin-based triple antithrombotic strategy. Therefore, the current expert opinions and consensus of North American Societies recommend a NOAC plus a P2Y12 inhibitor in patients with AF and PCI. In the present study, Rivaroxaban + Clopidogre are required for 45 days in LAAO group after LAAO.<br>Drug: Aspirin + Clopidogrel<br>* Aspirin + Clopidogrel are required from 46 days to 12 months after LAAO.<br>|
| Active Comparator: Novel oral anti-coagulation (NOAC)-based anti-thrombotic therapy<br>Drug: Rivaroxaban 15 mg QD + Clopidogrel 75mg QD for 12 months | Drug: Rivaroxaban + Clopidogre<br>* Previous pivotal trials have shown that in patients with atrial fibrillation and requiring antiplatelet treatment, a NOAC plus clopidogrel regimen was associated with a lower incidence of bleeding events as compared with a warfarin-based triple antithrombotic strategy. Therefore, the current expert opinions and consensus of North American Societies recommend a NOAC plus a P2Y12 inhibitor in patients with AF and PCI. In the present study, Rivaroxaban + Clopidogre are required for 45 days in LAAO group after LAAO.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major adverse cardiac and cerebrovascular events (MACCE) | MACCE define as a composite endpoint of any death, any stroke, any myocardial infarction (MI), and systemic embolism (SE). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BARC type 2, 3 or 5 bleeding events | Powered Key secondary endpoint, Bleeding Academic Research Consortium (BARC) defined type 2, 3, 5 bleeding events | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Left atrial appendage occlusion, Percutaneous coronary intervention, Novel oral anti-coagulation, Atrial Fibrillation