Clinical Significance and Prognosis of Right Heart Thrombi Associated With Acute Pulmonary Thromboembolism　- Results of a Multicenter Registry of Thrombolysis in Japan.

BACKGROUND: Thrombolytic therapy is standard treatment in acute pulmonary thromboembolism (PTE) with hemodynamic instability. Although right heart thrombi (RHT) appear to increase mortality in acute PTE, large-scale studies of acute PTE with RHT are scarce.Methods and Results:Patient data (from August 2005 to May 2014) obtained from post-marketing surveillance of thrombolytic therapy using a tissue-type plasminogen activator were analyzed retrospectively. Of the 2,698 confirmed cases of acute PTE who underwent echocardiographic assessment, 166 (6.2%) were diagnosed with RHT. PTE patients with RHT, compared with those without RHT, had higher rates of mortality (20.2% vs. 10.4%, P<0.001), hemodynamic instability (53.0% vs. 37.7%, P<0.001), and PTE recurrence (6.6% vs. 2.3%, P=0.003). When considering PTE-related hemodynamic severity (cardiopulmonary arrest/collapse, massive, submassive, and non-massive), mortality was significantly higher in patients with RHT in the massive (19.8% vs. 7.7%, P=0.002) and submassive (8.0% vs. 2.8%, P=0.018) groups, whereas no significant differences was found between those with and without RHT in the cardiopulmonary arrest/collapse (51.7% vs. 52.1%, P=0.960) and non-massive (1.6% vs. 0%, P=0.596) groups. CONCLUSIONS: PTE patients with RHT had higher mortality, severity, and PTE recurrence rates. RHT was particularly associated with worse outcomes in patients with massive or submassive PTE.

Observational investigation of thrombolysis with the tissue-type plasminogen activator monteplase for acute pulmonary embolism in Japan.

BACKGROUND: In Japan, the safety and efficacy of thrombolytic therapy using tissue-type plasminogen activator for acute pulmonary embolism (PE) in the real world remain unclear. METHODS AND RESULTS: A total of 1,254 patients with acute PE covered by the post-marketing surveillance of thrombolytic therapy using monteplase were divided into 3 groups: cardiopulmonary arrest (CPA)/collapse group (n=85); massive group, patients with unstable hemodynamics without CPA/collapse (n=217); and submassive group, patients with stable hemodynamics and right ventricular dysfunction (RVD) (n=465). In the efficacy analysis of 767 cases, the response rate to monteplase was 94.6% according to pulmonary circulation assessment and 93.3% according to clinical efficacy judged by symptoms and signs. Overall survival rates at 30 days after monteplase administration were 89.2% overall, 41.2% for the CPA/collapse group, 93.0% for the massive group, and 96.3% for the submassive group. When the safety of monteplase was analyzed in 1,241 cases, severe bleeding complications occurred in 100 patients (8.1%). Intracranial hemorrhage (ICH) occurred in 21 patients (1.7%), but no significant independent predictors were found in multivariate analysis. CONCLUSIONS: Thrombolytic therapy is highly effective in Japanese acute PE patients and offers acceptable safety, but attention is needed regarding severe bleeding complications, including ICH.

Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats.

Thrombin is a powerful agonist for a variety of cellular responses including platelet aggregation and vascular smooth muscle cell (SMC) proliferation. These actions are mediated by a thrombin receptor known as protease-activated receptor-1 (PAR-1). Recently we discovered that 1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl)ethanone hydrobromide (E5555, atopaxar) is a potent and selective thrombin receptor antagonist. This study characterized the pharmacological effects of E5555 on SMC proliferation in vitro and in a rat model of intimal thickening after balloon injury in vivo. E5555 selectively inhibited rat aortic SMC proliferation induced by thrombin and thrombin receptor-activating peptide (TRAP) with half maximal inhibitory concentration (IC(50)) values of 0.16 and 0.038 µM, respectively. E5555 did not inhibit rat SMC proliferation induced by basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) at concentrations up to 1µM. In addition, E5555 inhibited human aortic SMC proliferation induced by thrombin at concentrations of 0.3 and 3units/ml with IC(50) values of 0.028 and 0.079 µM, respectively, whereas it did not affect bFGF-induced proliferation at concentrations up to 1µM. Repeated oral administration of 30 mg/kg E5555 (once daily for 16 days) significantly reduced neointimal formation in the balloon-injured rat arterial model. These results suggested that a PAR-1 antagonist could be effective for treating restenosis following vascular intervention in addition to preventing thrombus formation. E5555 could thus have therapeutic potential for restenosis and chronic atherothrombotic disease.