EPIDAURUS trial halted over bleeding risk

The EPIDAURUS randomized controlled trial was terminated early in September 2025 after enrolling 602 patients, according to a report in Nature Medicine. An independent Data and Safety Monitoring Board recommended stopping the trial due to safety signals, including greater numbers of deaths, ischemic strokes, and bleeding events in the experimental treatment group.

Researchers designed the trial to test a dual antithrombotic therapy (DAT) strategy. They compared a one-month regimen of a direct oral anticoagulant (DOAC) plus a potent P2Y12 inhibitor (prasugrel or ticagrelor) against a control regimen of a DOAC plus clopidogrel and in-hospital aspirin. The study aimed to see if the more potent antiplatelet combination could reduce ischemic events without a relevant increase in bleeding complications.

Study Design and Early Termination

The open-label trial was conducted across 37 medical centers in Germany and Austria between December 2021 and September 2025. It was planned to enroll 1,474 patients by the end of 2027 but was halted prematurely. The sponsor accepted the monitoring board's recommendation and stopped recruitment immediately. The board based its decision on a low likelihood of the experimental intervention proving superior and consistent safety concerns.

Of the 602 patients in the full analysis set, 302 were assigned to the experimental group and 300 to the control group. The median age was 78 years, and 154 patients (26%) were female. Protocol deviations were higher in the experimental group (24 versus 2).

Key Safety Findings

Exploratory analyses of secondary safety endpoints revealed the core problem. Treatment with a potent P2Y12 inhibitor was associated with higher bleeding rates compared to clopidogrel and in-hospital aspirin. This was assessed using the Bleeding Academic Research Consortium scale for type 2 or greater bleeding. The researchers found no clear reduction in the risk of ischemic complications to offset this increased bleeding danger.

The source states these findings do not support the routine use of potent P2Y12 inhibitors in combination with DOACs for this specific patient population. This outcome addresses a significant evidence gap noted in recent guideline updates. The 2020 European Society of Cardiology guidelines had considered recommending this combination for high-risk patients, but the recommendation was removed in 2023 due to limited supporting data.

Patient Management and Adherence

Adherence to the assigned drug strategy was high in both groups. At day seven after randomization, 96.2% of patients in the experimental group were receiving a potent P2Y12 inhibitor, and 99.3% in the control group were on clopidogrel. According to the protocol, patients in the experimental group were to switch from prasugrel or ticagrelor to clopidogrel after one month. Of the 277 patients who reached day 34, 260 (93.9%) had successfully switched. For broader context on clinical trial outcomes, our stats page provides related data.

The trial's termination underscores the persistent challenge of balancing stroke prevention and bleeding risk in patients with both atrial fibrillation and acute coronary syndrome. The report confirms that the search for an optimal antithrombotic regimen continues, as detailed in our fixtures of ongoing research. Oral anticoagulation was paused or discontinued in 17 patients in the experimental group and in six patients in the control group during the study.