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.

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