Triple vs. Dual Therapy
Condition: Atrial Fibrillation; Acute Coronary Syndrome
MeSH terms: Atrial Fibrillation; Acute Coronary Syndrome
Study type: Interventional
Phase: Phase 1

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 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
    


Intervention name(s): Ticagrelor + Apixaban + ASA; Ticagrelor + Apixaban
Intervention type(s): Drug; Drug
Intervention MeSH terms: Apixaban; Ticagrelor
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Apixaban; Ticagrelor; ASA; shed blood; perfusion chamber