Antithrombotic Triple Therapy in Humans
Condition: Atrial Fibrillation; Acute Coronary Syndrome
MeSH terms: Atrial Fibrillation; Acute Coronary Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    


Intervention name(s): Dabigatran, Ticagrelor, ASA; Rivaroxaban, Ticagrelor, ASA; Phenprocoumon, Ticagrelor, ASA
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Rivaroxaban; Dabigatran; Phenprocoumon; Ticagrelor
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science