title: Antithrombotic properties of rafigrelide: a phase 1, open-label, non-randomised, single-sequence, crossover study.
abstract: Platelets play a central role in atherothrombotic events. We investigated the effect of a novel platelet-lowering agent, rafigrelide, on thrombus formation and characteristics. In this phase 1, open-label, non-randomised, single-sequence, crossover study, healthy male volunteers received rafigrelide for 14 days (Period 1). Following a ≥6-week washout period, they then received rafigrelide + acetylsalicylic acid (ASA) for 14 days (Period 2). Thrombus formation was assessed ex vivo using the Badimon perfusion chamber, and thrombus characteristics were assessed using thromboelastography. A total of 15 volunteers were enrolled in the study and were assigned to Panel A or Panel B, which had different schedules of assessments. In Panel A, after treatment with rafigrelide alone (Period 1), mean (± standard deviation) platelet count was reduced from 283 (± 17) × 10⁹/l at Day 1, to 125 (± 47) × 10⁹/l at Day 14 (n=6) and thrombus area reduced under high and low shear conditions. Reductions in thrombus area under high shear conditions correlated with reductions in platelet count (r²=0.11, p=0.022; n=12). Rafigrelide treatment prolonged clot formation time and reduced clot strength. The addition of ASA to rafigrelide (Period 2) had no additional effect on platelet count or thrombus area under high or low shear conditions. Similar results were seen in Panel B for all parameters. The most common adverse events (≥3 participants per period) were thrombocytopenia and headache. While confirming the platelet-lowering effects of rafigrelide, this early phase study also indicates that rafigrelide has antithrombotic properties under both high and low shear conditions.
authors.forename: K
authors.initials: K
authors.lastname: Balasubramaniam
authors.forename: G
authors.initials: G
authors.lastname: Viswanathan
authors.forename: J
authors.initials: J
authors.lastname: Dragone
authors.forename: R
authors.initials: R
authors.lastname: Grose-Hodge
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.forename: S
authors.initials: S
authors.lastname: Troy
authors.forename: P
authors.initials: P
authors.lastname: Preston
authors.affiliation: Azfar G. Zaman, MD, FRCP, Consultant Cardiologist and Honorary Reader, Freeman Hospital and Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, NE7 7DN, United Kingdom, Tel.: +44 191 2137277, Fax: +44 191 2231417, E-mail: azfar.zaman@nuth.nhs.uk.
authors.forename: A G
authors.initials: AG
authors.lastname: Zaman
mesh_terms: D000328:Adult; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D006261:Headache / Q000209:etiology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010976:Platelet Count; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D013916:Thrombelastography; D013921:Thrombocytopenia / Q000209:etiology; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; C021139:anagrelide; D001241:Aspirin; C000597289:rafigrelide
keywords: Badimon perfusion chamber; Rafigrelide; platelet-lowering; thromboelastography; thrombus formation