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Thrombin-induced platelet activation is initiated by PAR1 and PAR4 receptors. Vorapaxar, a PAR1 antagonist, has been assessed in patients with acute coronary syndromes (ACS) and stable atherosclerotic disease in addition to standard-of-care treatment. In clinical trials, vorapaxar has been observed to reduce the frequency of ischaemic events in some subgroups though in others has increased the frequency of bleeding events. Among patients undergoing CABG surgery, which is associated with excess thrombin generation, bleeding was not increased. The aim of these studies was to investigate the effects of selective PAR1 antagonism on thrombin-induced platelet activation in patients receiving vorapaxar or placebo in the TRACER trial and to explore the roles of PAR1 and PAR4 in thrombin-induced platelet activation in healthy volunteers. ACS patients receiving vorapaxar or placebo in the TRACER trial were studied at baseline and 4 hours, 1 and 4 months during drug administration. Thrombin-induced calcium mobilisation in platelet-rich plasma was assessed by flow cytometry. In vitro studies were performed in healthy volunteers using the PAR1 antagonist SCH79797 or PAR4 receptor desensitisation. Vorapaxar treatment significantly inhibited thrombin-induced calcium mobilisation, leaving a residual, delayed response. These findings were consistent with calcium mobilisation mediated via the PAR4 receptor and were reproduced in vitro using SCH79797. PAR4 receptor desensitization, in combination with SCH79797, completely inhibited thrombin-induced calcium mobilisation confirming that the residual calcium mobilisation was mediated via PAR4. In conclusion vorapaxar selectively antagonises the PAR1-mediated component of thrombin-induced platelet activation, leaving the PAR4-mediated response intact, which may explain why vorapaxar is well tolerated in patients undergoing CABG surgery since higher thrombin levels in this setting may override the effects of PAR1 antagonism through PAR4 activation, thus preserving haemostasis. Further assessment may be warranted. [ABSTRACT FROM AUTHOR]

Aims To explore variations in invasive care of the elderly with acute coronary syndromes across international practice. [ABSTRACT FROM PUBLISHER]

: ObjectivesWe sought to assess the incidence and clinical significance of elevated cardiac troponin I (cTnI) after percutaneous coronary intervention (PCI).: BackgroundElevated creatine kinase-MB (CK-MB) is prognostically important after PCI, but the prognostic significance of elevated cTnI after PCI is uncertain.: MethodsIn a prospective substudy of the Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) trials, which randomized patients with acute coronary syndromes (ACS) to receive aspirin or sibrafiban, we measured cTnI (positive, ≥1.5 ng/ml) and CK-MB (positive, ≥7 ng/ml) in 481 patients with PCI. Samples were collected immediately before and at 0, 8 and 16 h after PCI and analyzed by a core laboratory. The primary end point was the Kaplan-Meier estimate of death, myocardial infarction or severe, recurrent ischemia at 90 days.: ResultsOverall, 230 patients (48%) had elevated cTnI after PCI. Such patients underwent PCI sooner and were more likely to have coronary stenting. Elevated cTnI was associated with nonsignificantly higher risks of the primary end point (11.5% vs. 8.7%; p = 0.15) and of death (1.8% vs. 0.4%; p = 0.4) and a significantly higher risk of death or infarction (10.6% vs. 4.2%; p = 0.005). This pattern was more pronounced for patients who became positive only after PCI: primary end point, 20.7% vs. 10.1% for patients who remained negative after PCI (p = 0.05); death, 5.2% vs. 0% (p = 0.02); death or infarction, 18.1% vs. 4.1% (p = 0.007).: ConclusionsElevated cTnI, often observed after PCI in patients with ACS, is associated with worse 90-day clinical outcomes. This marker, therefore, is a useful prognostic indicator in such patients. [Copyright &y& Elsevier]

Background: Vorapaxar is a PAR-1 antagonist that is approved for secondary prevention of cardiovascular events but has been associated with increased intracranial hemorrhage. Methods: The TRACER trial compared vorapaxar vs. placebo among patients with ACS. Strokes were adjudicated by a central events committee. Stroke severity was assessed by sites using the modified Rankin score. Results: Of 12,944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up 477 days). Four patients had a single stroke of unknown type; 195 had ≥1 stroke (165 non-hemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96/6473 (1.5%) patients assigned vorapaxar and 103/6471 (1.6%) patients assigned placebo. Vorapaxar-assigned patients had a higher proportion of hemorrhagic strokes (22/96 [22.9%] vs. 8/103 [7.8%]) and a lower proportion of non-hemorrhagic stroke (74/96 [77.1%] vs. 93/103 [90.3%]). Kaplan-Meier incidence of stroke for vorapaxar vs. placebo was higher for hemorrhagic stroke, lower but not significantly different for non-hemorrhagic stroke, and similar for stroke overall (Figure 1). Rankin scores at discharge were reported in 59/96 strokes with vorapaxar and 64/103 strokes with placebo. More than half of patients in each group reported less than moderate disability (Rankin 0-2; 59% [35/59] vorapaxar vs. 55% [35/64] placebo); moderate to severe disability (Rankin 3-5) was reported in 29% (17/59) and 31% (20/64); and death (Rankin 6) was reported in 11.9% (7/59) and 14.1% (9/64). Conclusion: Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a non-significant trend toward lower non-hemorrhagic stroke. Overall stroke frequency and severity were similar with vorapaxar vs. placebo. [ABSTRACT FROM AUTHOR]