What is the Optimal Antithrombotic Strategy in Patients With Atrial Fibrillation Undergoing PCI?

Study Overview
=================
Brief Summary
-----------------
The optimal antithrombotic management in patients with coronary artery disease (CAD) and concomitant atrial fibrillation (AF) is unknown. AF patients are treated with oral anticoagulation (OAC) to prevent ischemic stroke and systemic embolism and patients undergoing percutaneous coronary intervention (PCI) are treated with dual antiplatelet therapy (DAPT), i.e. aspirin plus P2Y12 inhibitor, to prevent stent thrombosis (ST) and myocardial infarction (MI). Patients with AF undergoing PCI were traditionally treated with triple antithrombotic therapy (TAT, i.e. OAC plus aspirin and P2Y12 inhibitor) to prevent ischemic complications. However, TAT doubles or even triples the risk of major bleeding complications. More recently, several clinical studies demonstrated that omitting aspirin, a strategy known as dual antithrombotic therapy (DAT) is safer compared to TAT with comparable efficacy. However, pooled evidence from recent meta-analyses suggests that patients treated with DAT are at increased risk of MI and ST. Insights from the AUGUSTUS trial showed that aspirin added to OAC and clopidogrel for 30 days, but not thereafter, resulted in fewer severe ischemic events. This finding emphasizes the relevance of early aspirin administration on ischemic benefit, also reflected in the current ESC guideline. However, because we consider the bleeding risk of TAT unacceptably high, we propose to use a short course of DAPT (omitting OAC for 1 month). There is evidence from the BRIDGE study that a short period of omitting OAC is safe in patients with AF. In this study, these patients are treated with DAPT, which also prevents stroke, albeit not as effective as OAC. This temporary interruption of OAC will allow aspirin treatment in the first month post-PCI where the risk of both bleeding and stent thrombosis is greatest. The WOEST 3 trial is a multicentre, open-label, randomised controlled trial investigating the safety and efficacy of one month DAPT compared to guideline-directed therapy consisting of OAC and P2Y12 inhibitor combined with aspirin up to 30 days. We hypothesise that the use of short course DAPT is superior in bleeding and non-inferior in preventing ischemic events. The primary safety endpoint is major or clinically relevant non-major bleeding as defined by the ISTH at 6 weeks after PCI. The primary efficacy endpoint is a composite of all-cause death, myocardial infarction, stroke, systemic embolism, or stent thrombosis at 6 weeks after PCI.

Official Title
-----------------
What is the Optimal Antithrombotic Strategy in Patients With Atrial Fibrillation Having Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention?

Conditions
-----------------
Acute Coronary Syndrome, Myocardial Infarction, Atrial Fibrillation, Atrial Flutter, STEMI - ST Elevation Myocardial Infarction, NSTEMI - Non-ST Segment Elevation MI, Bleeding, Stroke, Stent Thrombosis, Embolism, Coronary Artery Disease

Intervention / Treatment
-----------------
* Drug: 30-day DAPT
* Drug: Guideline-directed therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients ≥ 18 years Undergoing successful PCI (either ACS or elective PCI) History of or newly diagnosed (<72 hours after PCI/ACS) atrial fibrillation or flutter with a long-term (≥ 1 year) indication for OAC Exclusion Criteria: Contra indication to edoxaban, aspirin or all P2Y12 inhibitors Current indication for OAC besides atrial fibrillation/flutter (e.g. venous thromboembolism) <12 months after any stroke CHADSVASc score ≥7 Moderate to severe mitral valve stenosis (AVA ≤1.5 cm2) Mechanical heart valve prosthesis Intracardiac thrombus or apical aneurysm requiring OAC Poor LV function (LVEF <30%) with proven slow-flow History of intracranial haemorrhage Active bleeding on randomization History of intraocular, spinal, retroperitoneal, or traumatic intra-articular bleeding, unless the causative factor has been permanently resolved Recent (<1 month) gastrointestinal haemorrhage, unless the causative factor has been permanently resolved. Known coagulopathy Severe anaemia requiring blood transfusion or thrombocytopenia <50 × 109/L BMI >40 or bariatric surgery Kidney failure (eGFR <15) Active liver disease (ALT, ASP, AP >3x ULN or active hepatitis A, B or C) Active malignancy excluding non-melanoma skin cancer Life expectancy <1 year Pregnancy or breast-feeding women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is designed as a multicentre open label randomized controlled superiority trial with regards to safety and non-inferiority trial with regards to efficacy. Participating study centres will enrol patients undergoing PCI who have previously or newly diagnosed AF and indication for NOAC. As soon as possible, but within 72 hours after PCI, patients will be randomized 1:1 to either 30 days DAPT (asprin + P2Y12 inhibitor), followed by guideline-directed therapy (edoxaban + P2Y12 inhibitor) Standard guideline-directed therapy (edoxaban + P2Y12 inhibitor, aspirin limited to in-hospital use or up to 30 days in selected high-risk patients)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: First month DAPT<br>30-day DAPT (aspirin + P2Y12 inhibitor). After 30 days all patients will be treated with edoxaban and P2Y12 inhibitor. Selection of P2Y12 inhibitor is at the discretion of the treating physician, depending on both bleeding and ischemic risk. Dosage of aspirin and P2Y12 inhibitor is according to local guidelines. NOAC of choice will be edoxaban. Patients will be treated with the recommended dose of 60mg once daily or the reduced dose of 30mg once daily. | Drug: 30-day DAPT<br>* DAPT (aspirin + P2Y12 inhibitor) during the first 30 days following PCI. After 30 days, all patients will be treated with edoxaban and a P2Y12 inhibitor.<br>|
| Active Comparator: Guideline-directed therapy<br>Standard guideline-directed therapy (edoxaban + P2Y12 inhibitor, aspirin limited to in-hospital use or up to 30 days in selected high-risk patients). After 30 days all patients will be treated with edoxaban and P2Y12 inhibitor. Selection of P2Y12 inhibitor is at the discretion of the treating physician, depending on both bleeding and ischemic risk. Dosage of aspirin and P2Y12 inhibitor is according to local guidelines. NOAC of choice will be edoxaban. Patients will be treated with the recommended dose of 60mg once daily or the reduced dose of 30mg once daily. | Drug: Guideline-directed therapy<br>* Guideline-directed therapy (edoxaban + P2Y12 inhibitor, aspirin limited to in-hospital use or up to 30 days in selected high-risk patients)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary safety endpoint | Major or clinically relevant non-major bleeding as defined by the International Society of Thrombosis and Haemostasis | 6 weeks | 
| Primary efficacy endpoint | Composite of all-cause death, myocardial infarction, stroke, systemic embolism, or stent thrombosis | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding complications | Major or clinically relevant non-major bleeding as defined by the International Society of Thrombosis and Haemostasis | 6 months | 
| Thrombotic complications | Composite of all-cause death, myocardial infarction, stroke, systemic embolism, or stent thrombosis | 6 months | 
| Net clinical benefit | Composite of major bleeding, myocardial infarction, stroke, systemic embolism all-cause death and stent thrombosis | 6 weeks, 3 months, 6 months | 
| Clinical symptom severity | CCS grade | 6 weeks, 3 months, 6 months | 
| All-cause death | All-cause death as defined by ARC-2 and SCTI | 6 weeks, 3 months, 6 months | 
| Myocardial infarction | Myocardial infarction as defined by the 4th Universal Definition of Myocardial Infarction | 6 weeks, 3 months, 6 months | 
| Stroke | Stroke as defined by VARC-2 definitions | 6 weeks, 3 months, 6 months | 
| Systemic embolism | Systemic embolism according to ENTRUST-AF PCI definition | 6 weeks, 3 months, 6 months | 
| Stent thrombosis | Stent thrombosis as defined by ARC-2 | 6 weeks, 3 months, 6 months | 
| Major bleeding | Major bleeding as defined by BARC 3 or 5 | 6 weeks, 3 months, 6 months | 
| Clinically relevant non-major bleeding | CRNM as defined by BARC 2 | 6 weeks, 3 months, 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Coronary Syndrome, Myocardial Infarction, Atrial Fibrillation, Atrial Flutter, STEMI - ST Elevation Myocardial Infarction, NSTEMI - Non-ST Segment Elevation MI, Oral Anticoagulant, NOAC - Novel Oral Anticoagulant, DOAC - Direct Oral Anticoagulant, DAPT - Dual Antiplatelet Therapy, Antithrombotic Therapy, Dual Therapy, Triple Therapy, Bleeding, Thrombosis, Stroke, Stent Thrombosis, Systemic Embolism, Percutaneous coronary intervention, Coronary artery disease