Aspirin/Propoxyphene Napsylate

This trial will enroll approximately 6,000 patients with recent embolic stroke of unknown source (ESUS). Patients will be randomized to dabigatran or acetylsalicyclic acid (ASA) (1:1 ratio) and have visits every three months. The study doctor may prescribe blinded concomitant ASA for pts with coronary artery disease but this is not mandatory. All Adverse Events (AEs), Serious Adverse Events (SAEs), outcome events will be recorded. The trial will conclude when the required number of stroke events are positively adjudicated which is estimated to take 3 years (including 2.5 years of enrollment).

Background:
The acute coronary syndrome (ACS) is a complication of coronary artery disease (CAD) and associated with increased mortality. Dual antiplatelet therapy of acetylsalicylic acid (ASA) with P2Y12 receptor antagonists such as clopidogrel is a cornerstone in the treatment of patients with advanced CAD. Due to delayed onset of action, intersubject variability or resistance to clopidogrel, different platelet aggregation inhibitors have been developed. Ticagrelor is a reversible P2Y12 receptor antagonist with superior efficacy compared to clopidogrel in the prevention of cardiovascular death in these patients.
Atrial fibrillation (AF) is also associated with thromboembolic events and substantial mortality. Beside vitamin K antagonists (VKA, phenprocoumon) for stroke prevention in patients with AF, the direct factor Xa inhibitor apixaban has recently received approval for prophylactic treatment of patients with non-valvular AF.
However, there is a lack of efficacy or safety data for the combined impact of antithrombotic drugs in patients requiring arterial and venous thromboembolic prophylaxis due to their underlying co-morbidities. One trial suggests treatment with VKA + clopidogrel without ASA as equal effective as antithrombotic triple therapy (with ASA) in this population. However, the effect in combination with novel oral anticoagulants has not been investigated so far.
Study objectives:
To evaluate the effect of ticagrelor + apixaban in combination with or without ASA at steady state on markers of coagulation activation and on thrombus size in an ex vivo perfusion chamber experiment. Additionally, plasma samples will be analysed for PK-data (ticagrelor & apixaban concentrations)
Study design:
A single-centre, prospective, sequential, controlled, analyst-blinded study in two groups. Subjects will receive ticagrelor + apixaban in combination with (study A) or without (study B) ASA. All IMPs will be administered at doses indicated for stroke prevention in AF (lower dose: 2.5mg due to ethical concerns) or ACS. Markers on thrombin generation and platelet activation will be studied in venous blood where coagulation is in resting state and in shed blood where the clotting system is activated in the microvasculature in vivo: prothrombin fragment 1+2 (F1+2), thrombin-anti-thrombin (TAT), β-thromboglobulin (β-TG). Additionally, inhibition of factor Xa activity and concentrations of ticagrelor and apixaban will be assessed in venous blood. Further, thrombus size of clots formed in an ex vivo perfusion chamber will be determined by measurement of D-Dimer and p-Selectin levels.
Study population A total of 40 healthy, non-smoking and drug-free male volunteers will be enrolled (study A and B; n = 20 per group).
Main outcome variables:
β-TG in shed blood
Additional outcome variables:
F1+2 and TAT in shed blood
fibrin formation (D-Dimer) and platelet deposition (p-Selectin) in an ex vivo perfusion chamber model of thrombosis
β-TG, F1+2, TAT & inhibition of factor Xa in venous blood
PT, aPTT and ACT in venous blood
ticagrelor & apixaban plasma concentrations
shed blood volume