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 rivaroxaban and the direct thrombin
inhibitor dabigatran have 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.
Study objectives: To evaluate the effect of ticagrelor + ASA in combination with dabigatran,
rivaroxaban or phenprocoumon at steady state on markers of coagulation activation. The
effects on coagulation activation will also be studied after a single dose of dabigatran,
rivaroxaban or ticagrelor and at a therapeutic INR of phenprocoumon.
Study design: A single-centre, prospective, randomized, controlled, analyst-blinded study in
three parallel-groups. Subjects will receive ticagrelor + ASA in combination with dabigatran
(treatment A), rivaroxaban (treatment B) or phenprocoumon (treatment C). All IMPs will be
administered at doses indicated for stroke prevention in AF 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), D-Dimer, thromboxane B2 (TxB2), CD40 ligand (CD40L), p-Selectin.
Further, the endogenous thrombin potential (ETP), inhibition of factor Xa activity, activated
partial thromboplastin time (aPTT), prothrombin time (PT), Biophen® and Hemoclot® will be
assessed in venous blood.
Study population: A total of 60 healthy, non-smoking and drug-free male volunteers will be
enrolled in this trial and randomized into one of three balanced groups (treatment A, B and
C; n = 20 per group).
Main outcome variables: β-TG, F1+2 and TAT in shed blood
Additional outcome variables:
- D-Dimer, TxB2, CD40L and p-Selectin in shed blood
- β-TG, F1+2, TAT, D-Dimer, TxB2, CD40L, p-Selectin, ETP, aPTT, PT, inhibition of factor
Xa, Biophen® and Hemoclot® in venous blood
Risk/ benefit assessment:Total blood loss will be, dependent on treatment allocation, between
330 ml and 510 ml throughout the entire study period of 4 - 5 weeks. This amount of venous
blood is considered to be acceptable in this healthy population. Blood sampling procedures
may cause mild and transient pain. A minor haematoma may occur at the site of needle
insertions. Bleeding time incisions may leave small persistent scars. Administration of the
study drugs, in particular as triple combination for 5 days, results in transient
hypocoagulability and may cause overt or occult bleeding. The risk is considered low in the
healthy subjects under study. Continuous monitoring of safety parameters (haemoglobin,
haematocrit, platelet count, coagulation) and surveillance of the overall status will be
performed during study participation. Subjects will be instructed to avoid vigorous physical
exercise and handling of hazardous machinery during study participation. ASA, dabigatran and
rivaroxaban can cause gastrointestinal discomfort. Other side effects are rare.
The combination of these novel anticoagulants (dabigatran, rivaroxaban, ticagrelor) has not
been investigated so far. Conducting this study in a healthy population limits potential
bleeding risk reported from drug interactions and impaired liver or renal function, which may
influence the pharmacokinetics and -dynamics of the investigational products.
This study can provide information on haemostatic system activation in vivo during triple
treatment with antithrombotic drugs, which is indicated for patients with AF and ACS. The
results of this study may provide dosing guidance for risk reduction of patients with ACS and
AF.