Ticagrelor in Human Endotoxemia Response to Human Endotoxemia

Rationale: In patients suffering a myocardial infarction the P2Y12 receptor antagonists prasugrel and ticagrelor improve outcome and prognosis compared to clopidogrel. Moreover, ticagrelor lowers mortality from pulmonary infections and sepsis, which cannot solely be explained by its platelet-inhibiting effect. An effect on the inflammatory response in the setting of acute myocardial might underlie this phenomenon and if substantiated support a novel beneficial mechanism of the new the P2Y12 receptor antagonists. Objective: To study whether ticagrelor, added to acetylsalicylic acid, modulates the inflammatory response to the administration of lipopolysaccharide (LPS) in humans in vivo, and to compare this effect with the P2Y12 antagonist clopidogrel. Study design: Prospective randomized placebo-controlled trial, according to a PROBE design (prospective randomized open blinded-endpoint study). Study population: Forty healthy male volunteers aged ≥ 18 and ≤ 35 years. Intervention (if applicable): Participants will be randomized to receive either placebo (twice daily), acetylsalicylic acid (80 mg once daily, after a loading dose of 160 mg) + placebo (once daily), acetylsalicylic acid (80 mg once daily, after a loading dose of 160 mg) + ticagrelor (90 mg twice daily, after a loading dose of 180 mg) or acetylsalicylic acid (80 mg once daily, after a loading dose of 160 mg)+ clopidogrel (75 mg once daily, after a loading dose of 300mg). Main study parameters/endpoints: Endpoints: area under the curve of the proinflammatory cytokines TNF-alpha, IL6, IL-10, IL1ra IL-8, IL-1β, MCP-1 MIP-1a, MIP-1b en IFN; peak concentrations of the various cytokines; plasma concentration of HMGP1; platelet-monocyte complex formation and markers of platelet function; plasma concentration of adenosine.

7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg.

7 day treatment with clopidogrel x75 mg after a loading dose of 300 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg

ex vivo stimulation of platelets with ADP and collagen, response measured as P-selectin and fibrinogen)

difference between measurement prior to start of study drug after challenge with endotoxin at day 7 of medication

Inclusion Criteria: Age ≥ 18 and ≤ 35 years Male No known current medical/psychiatric diseases Exclusion Criteria: History, signs or symptoms of any cardiovascular disease History of chronic obstructive pulmonary disease (COPD) or asthma History of hemorrhagic diathesis, or any other disorder associated with increased risk of bleeding Previous spontaneous vagal collapse Use of any medication Smoking Liver enzyme abnormalities (defined as ALAT and/or ASAT > twice upper limit of normality) Thrombocytopenia (<150*109 /ml) or anemia (haemoglobin < 8.0 mmol/L) Any obvious disease associated with immune deficiency Febrile illness in the week before the LPS challenge Hypersensitivity to ticagrelor or any excipients Active pathological bleeding History of intracranial haemorrhage History of dyspepsia quantitative bleeding assessment tool (BAT) score >3 (see Appendix 1) Participation in another drug trial or donation of blood 3 months prior, until 3 months after the planned LPS challenge Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block, third degree atrioventricular block or a complex bundle branch block Hypertension (defined as RR systolic > 160 or RR diastolic > 90) Hypotension (defined as RR systolic < 100 or RR diastolic < 50) Renal impairment (defined as MDRD < 60 ml/min)