Escalated Single Platelet Inhibition for One Month Plus NOAC in Patients With Atrial Fibrillation and ACS Undergoing PCI

Study Overview
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Brief Summary
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The selection of the optimal antithrombotic therapy in patients with nonvalvular atrial fibrillation (AF) and acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is challenging. Until recently, triple antithrombotic therapy (TAT) consisting in Aspirin plus Clopidogrel plus OAC was considered the treatment of choice. While efficiently preventing ischaemic events, TAT is associated with an increase in bleeding complications. Therefore, in the past years several randomized controlled trials challenged TAT by comparing a triple antithrombotic therapy (TAT) regimen based on Vitamin K antagonists (VKA) to a dual antithrombotic regimen (DAT) based on non-vitamin K antagonist oral anticoagulants (NOACs) and P2Y12-inhibitors, mainly Clopidogrel in patients with AF undergoing PCI. However, approximately 30-40% of patients show low response to Clopidogrel and are not adequately protected against ischaemic events, in particular when presenting with ACS. This is supported by a recent meta-analysis reporting that TAT compared to DAT is associated with lower rates of stent thrombosis within 30 days after PCI. It is therefore reasonable to assume that a more potent platelet inhibition within the first month after PCI might reduce the rate of ischaemic complications observed in AF patients undergoing PCI, when receiving DAT. Moreover, a subsequent de-escalation to a less potent platelet inhibition one month after PCI might prevent an increase in bleeding complications. In EPIDAURUS the investigators will therefore test the hypothesis that DAT using NOAC plus an escalated antiplatelet therapy with a potent P2Y12-inhibitor for one month followed by Clopidogrel reduces ischaemic events without a relevant increase in bleeding complications in patients with AF and ACS undergoing PCI compared to standard DAT with NOAC plus Clopidogrel.

Official Title
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Escalated Single Platelet Inhibition for One Month Plus Direct Oral Anticoagulation in Patients With Atrial Fibrillation and acUte coRonary Syndrome Undergoing percutaneoUS Coronary Intervention

Conditions
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Acute Coronary Syndrome, Atrial Fibrillation

Intervention / Treatment
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* Drug: Prasugrel or Ticagrelor
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥ 18 years Atrial fibrillation requiring oral anticoagulation STEMI or NSTEMI (biomarker positive acute coronary syndrome) and successful completion of PCI (randomization will take place within 24h after successful PCI) Exclusion Criteria: Chronic renal insufficiency with glomerular filtration rate < 15 ml/min/1.73m2 History of ischaemic stroke or transient ischaemic attack (both contraindications for Prasugrel) and history of intracranial bleeding (contraindication for Ticagrelor) Contraindication for Clopidogrel or Aspirin Contraindication for P2Y12-inhibitor Severe chronic liver disease (Child-Pugh C) Indication for oral anticoagulation with Vitamin K antagonists Moderate to severe mitral stenosis or mechanical heart valve Any bleeding BARC type ≥ 2 within the last 4 weeks before index procedure Pregnancy or lactation Inability to cooperate with the protocol requirements Life expectancy < 6 months Participation in another investigational drug study Previous enrolment in this study For women of childbearing potential no negative pregnancy test and no agree to use a reliable method of birth control during the study Previous treatment with GP IIb/IIIa inhibitors within the last 12 hours A known genetic disorder involved in the metabolism of the study medication

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Potent P2Y12-Inhibition<br>Prasugrel 10mg (5 mg in patients ≥ 75 years old or weighing < 60 kg) q.d. per os or Ticagrelor 90mg bid per os | Drug: Prasugrel or Ticagrelor<br>* Escalated antiplatelet therapy with a potent P2Y12- inhibitor for one month in patients with atrial fibrillation and indication for treatment non-vitamin K antagonist oral anticoagulants (NOACs)<br>|
| Active Comparator: Clopidogrel<br>Clopidogrel 75mg q.d. per os | Drug: Clopidogrel<br>* Clopidogrel and NOAC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major ischaemic events defined as the composite of all-cause mortality, myocardial infarction, definite or probable stent thrombosis, ischaemic stroke and systemic thromboembolism | superiority test | 6 weeks | 
| Bleeding type 2 or higher according to the Bleeding Academic Research Consortium (BARC) criteria | non-inferiority test | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | 6 weeks | 
| Myocardial infarction |  | 6 weeks | 
| Definite or probable stent thrombosis |  | 6 weeks | 
| Ischaemic stroke |  | 6 weeks | 
| Systemic thromboembolism |  | 6 weeks | 
| Cardiovascular mortality |  | 6 weeks | 
| Bleeding type 2 or more according to the Bleeding Academic Research Consortium | superiority testing | 6 weeks | 
| Urgent revascularization |  | 6 weeks | 
| All-cause mortality |  | 6 months | 
| Unplanned hospitalization due to acute heart failure or acute coronary syndrome |  | 6 months | 
| Ischaemic stroke |  | 6 months |