Safety of the novel protease-activated receptor-1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke.

BACKGROUND: Vorapaxar, formerly SCH 530348, is a novel, orally active, potent thrombin receptor inhibitor selective for the protease-activated receptor-1 (PAR-1). Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events, particularly myocardial infarction, without increasing bleeding risk. The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin. METHODS: Ninety patients with previous ischemic stroke (≥14 days to <1 year before randomization) were randomized to receive vorapaxar (1 or 2.5 mg) or placebo once daily for 60 days. All patients received aspirin (75-150 mg/day). The primary endpoint was overall incidence of adverse events during the protocol-defined treatment phase (60 days). RESULTS: Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events, including serious adverse events. None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo. Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar. CONCLUSIONS: Vorapaxar used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke.

In vivo assessment of a multicomponent and nanostructural polymeric matrix as a delivery system for antimicrobials and bone morphogenetic protein-2 in a unicortical tibial defect in goats.

OBJECTIVE: To determine the response of cortical bone to a multicomponent and nanostructural polymeric matrix as a drug delivery system for enhancing bone healing. ANIMALS: 20 healthy adult crossbred goats. PROCEDURES: A 3.5-mm-diameter unicortical defect was created in each tibia (day 0), and goats (4 goats/group) were treated as follows: not treated (control group), grafted with the matrix, grafted with antimicrobial (tigecycline and tobramycin)-impregnated matrix, grafted with recombinant human bone morphogenetic protein type 2 (rhBMP-2)-impregnated matrix, or grafted with antimicrobial- and rhBMP-2-impregnated matrix. Elution kinetics of antimicrobials was monitored through plasma concentrations. Bone response was assessed with radiographic scoring (days 1 and 30) and dual-energy x-ray absorptiometry (days 1, 14, and 30). Goats were euthanized on day 30, and histomorphologic analysis was performed. Categorical variables were analyzed with a generalized linear model, and continuous variables were analyzed with an ANOVA. RESULTS: Plasma antimicrobial concentrations indicated continued release throughout the study. Radiography and dual-energy x-ray absorptiometry did not reveal significant differences among treatments on day 30. Periosteal reactions were significantly greater surrounding bone defects grafted with rhBMP-2-impregnated matrix than those not treated or grafted with matrix or with antimicrobial-impregnated matrix; periosteal reactions were similar in bone defects grafted with rhBMP-2-impregnated matrix and antimicrobial- and rhBMP-2-impregnated matrix. CONCLUSIONS AND CLINICAL RELEVANCE: The matrix served as an antimicrobial delivery system and stimulated bone proliferation when rhBMP-2 was present. Antimicrobial and rhBMP-2 can be used concurrently, but the presence of antimicrobials may affect the performance of rhBMP-2.

Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome.

AIM: A previous phase 2 study of patients undergoing non-urgent PCI treated with SCH530348 plus aspirin and clopidogrel tended to reduce MACE without increased bleeding. This study evaluated the safety of SCH530348 in Japanese patients with NSTE ACS. METHODS: Subjects (117), in whom PCI was planned, received standard-of-care (aspirin, ticlopidine, and heparin) and were randomized 4:1 to receive either SCH530348 (20 or 40 mg loading dose followed by 1 mg/d or 2.5 mg/d for 60 days) or placebo. The key safety endpoint was TIMI major and minor bleeding in the PCI cohort (n=92). The key exploratory efficacy endpoint was MACE and death within 60 days. Addition of SCH530348 to standard-of-care did not significantly increase the rate of TIMI major and minor bleeding (or non-TIMI bleeding) in the primary cohort. RESULTS: Incidence (non-MACE) and discontinuation of AEs were similar across groups. PCI subjects treated with SCH530348 plus standard-of-care experienced a significant reduction in periprocedural MI compared with standard-of-care alone (16.9% vs 42.9%, respectively; p=0.013). There were no deaths or any other MACE. CONCLUSION: SCH530348 added to standard-of-care did not result in excess bleeding in Japanese subjects with NSTE ACS but significantly reduced the incidence of periprocedural MI in subjects undergoing urgent PCI.

Basic and translational research on proteinase-activated receptors: antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease.

Atherothrombotic disease is a leading public health problem. Although current antiplatelet agents, such as aspirin and adenosine diphosphate (ADP)-receptor antagonists, reduce the morbidity and mortality associated with atherothrombotic disease, the residual risk for ischemic events remains substantial. The high residual risk despite dual antiplatelet therapy can be attributed to the fact that platelets possess multiple pathways of activation that are not all inhibited by aspirin and ADP-receptor antagonists. Among these, binding of thrombin to the proteinase-activated receptor 1 (PAR(1)) is the most potent platelet activation pathway. In addition, the PAR(1) pathway does not appear to be essential for initiating hemostasis. Inhibition of the PAR(1) receptor thus offers a possible new therapeutic approach with a potentially improved benefit-to-risk profile for treatment of patients with atherothrombotic disease. Preclinical and clinical studies have confirmed that SCH 530348, a potent, orally active thrombin-receptor antagonist selective for PAR(1), does not increase bleeding liability when added to dual antiplatelet therapy. Currently, two large ongoing phase 3 clinical trials are evaluating the efficacy and safety of SCH 530348 in combination with the standard of care in patients with acute coronary syndromes as well as for secondary prevention in patients with previous history of atherothrombotic disease.

Increasing incidence of club foot with higher population density: incidence and geographical variation in Denmark over a 16-year period--an epidemiological study of 936,525 births.

BACKGROUND: The occurrence of club foot (CF) varies between countries and populations, and may be related to endogenous and exogenous factors. We analyzed the occurrence of CF in a whole country over a long period of time (16 years). METHODS: Patients born in Denmark with a foot deformity 1978-93 were identified from the National Patient Register and the Register of Inborn Malformations. The records for each patient were studied in the hospital departments to establish the diagnoses and to obtain additional information. Demographic data were obtained from the Danish National Demographical Institute and from the Danish Population Register. RESULTS: The incidence of isolated CF was 1.2/1,000 live births. It increased significantly during the study period, and the incidence of CF and the standardized morbidity ratio for CF were significantly positively correlated to population densities in the counties and the districts. There was no significant increase in the relative proportion of children with CF born to non-Scandinavian parents during the period. INTERPRETATION: The increasing incidence of isolated CF with higher population density indicates that there may be exogenous factors that are pathogenic.