Potent antiplatelet therapy increases bleeding risk after heart attack in AF patients

Potent antiplatelet therapy increased bleeding without signs of benefit regarding cardiovascular events in patients with atrial fibrillation after a heart attack. This was the main finding of the EPIDAURUS trial presented in a Hot Line session today at ESC Congress 2026 and published simultaneously in Nature Medicine.

Atrial fibrillation (AF) affects almost 38 million people worldwide, with the prevalence predicted to double over the next 35 years. Principal Investigator, Professor Konstantinos Rizas from the Ludwig Maximilians University, Munich, Germany and the Cantonal Hospital St. Gallen, Switzerland, explained that the EPIDAURAS trial was conducted to fill an important gap in clinical knowledge: "Many patients who have AF receive direct oral anticoagulants to reduce their risk of stroke. Patients who have recently had a myocardial infarction (MI) receive antiplatelet therapy, in particular the combination of aspirin and a potent P2Y12 inhibitor, to reduce their risk of another ischemic event. But the optimal regimen for patients suffering from both AF and MI remains unclear." He noted that there is little evidence on the use of the potent P2Y12 inhibitors, prasugrel or ticagrelor, in combination with direct oral anticoagulants in these patients.

The EPIDAURUS trial compared a one-month regimen of a direct oral anticoagulant plus prasugrel or ticagrelor (experimental group) vs. a direct oral anticoagulant plus clopidogrel with in-hospital aspirin (control group). The direct oral anticoagulants, edoxaban, apixaban and rivaroxaban were permitted in the trial. Eligible patients had an indication for oral anticoagulation because of AF and had had an MI within 5 days of randomisation. The trial was conducted at 37 sites in Germany and Austria.

The study was prematurely terminated after enrolment of 602 of the planned 1,474 patients due to safety concerns raised by the Data and Safety Monitoring Board.

In the six weeks after randomization, the experimental group had higher rates of all secondary bleeding endpoints than the control group. The incidence of significant bleeding was more than threefold higher in the experimental group compared with the control group (Bleeding Academic Research Consortium 3 or more: hazard ratio 3.54; 95% confidence interval 1.15 to 10.85; p=0.028).

There was no difference between the groups for all primary and secondary efficacy endpoints at six weeks and six months when the effect of therapy was tested for various ischemic outcomes, such as cardiovascular death, MI and stroke.

In the first trial of its kind, we have answered an important clinical question. These findings do not support the routine use of potent P2Y12 inhibitors in combination with direct oral anticoagulants in patients with AF and MI."

Professor Konstantinos Rizas, Ludwig Maximilians University, Munich, Germany