Abstract
Background:
Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature.
Methods and results:
Platelet activation (β-thromboglobulin [β-TG]) and thrombin generation (prothrombin fragment 1 + 2 [F1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR 2.0-3.0). Coagulation biomarkers in shed blood were assessed at 3 h after monotherapy with the medicines under study, at 3 h after triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood β-TG and were more pronounced than phenprocoumon at an INR of 2.0-3.0. In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of β-TG, F1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough steady state.
Conclusion:
A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo.
Trial registration:
ClinicalTrials.gov NCT01812200.
Keywords:
aspirin; dabigatran; drug therapy, combination; phenprocoumon; rivaroxaban; ticagrelor.
© 2014 International Society on Thrombosis and Haemostasis.
Publication types
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Randomized Controlled Trial
MeSH terms
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Adenosine / administration & dosage
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Adenosine / adverse effects
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Adenosine / analogs & derivatives*
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Adenosine / pharmacokinetics
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Administration, Oral
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Adult
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Anticoagulants / administration & dosage*
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Anticoagulants / adverse effects
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Antithrombin III
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Aspirin / administration & dosage*
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Aspirin / adverse effects
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Austria
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Benzimidazoles / administration & dosage*
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Benzimidazoles / adverse effects
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Benzimidazoles / pharmacokinetics
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Biomarkers / blood
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Blood Coagulation / drug effects*
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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Dabigatran
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Drug Therapy, Combination
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Fibrinolytic Agents / administration & dosage*
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Fibrinolytic Agents / adverse effects
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Healthy Volunteers
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Humans
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International Normalized Ratio
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Male
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Morpholines / administration & dosage*
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Morpholines / adverse effects
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Morpholines / pharmacokinetics
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Peptide Fragments / blood
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Peptide Hydrolases / blood
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Phenprocoumon / administration & dosage*
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Phenprocoumon / adverse effects
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Platelet Activation / drug effects
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Platelet Aggregation Inhibitors / administration & dosage*
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Platelet Aggregation Inhibitors / adverse effects
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Prospective Studies
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Prothrombin
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Rivaroxaban
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Thiophenes / administration & dosage*
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Thiophenes / adverse effects
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Thiophenes / pharmacokinetics
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Thrombin / metabolism
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Thrombosis / blood
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Thrombosis / diagnosis
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Thrombosis / drug therapy*
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Ticagrelor
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Young Adult
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beta-Alanine / administration & dosage
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beta-Alanine / adverse effects
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beta-Alanine / analogs & derivatives*
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beta-Alanine / pharmacokinetics
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beta-Thromboglobulin / metabolism
Substances
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Anticoagulants
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Benzimidazoles
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Biomarkers
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Fibrinolytic Agents
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Morpholines
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Peptide Fragments
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Platelet Aggregation Inhibitors
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Thiophenes
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antithrombin III-protease complex
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beta-Thromboglobulin
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prothrombin fragment 1.2
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beta-Alanine
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Antithrombin III
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Prothrombin
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Rivaroxaban
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Peptide Hydrolases
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Thrombin
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Ticagrelor
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Dabigatran
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Adenosine
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Phenprocoumon
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Aspirin
Associated data
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ClinicalTrials.gov/NCT01812200
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EudraCT/2012-001814-41