e-Article
Inhibition of thrombin-activatable fibrinolysis inhibitor via DS-1040 to accelerate clot lysis in patients with acute pulmonary embolism: a randomized phase 1b study.
Document Type
Academic Journal
Author
Vanassche T; Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium. Electronic address: Thomas.vanassche@uzleuven.be.; Rosovsky RP; Thrombosis Research, Division of Hematology, Massachusetts General Hospital, Boston, Massachusetts, USA.; Moustafa F; Emergency Department, Clermont-Ferrand University Hospital, Clermont-Ferrand, France; Université Clermont Auvergne, Clermont-Ferrand, France.; Büller HR; Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.; Segers A; Itreas, Amsterdam, the Netherlands.; Patel I; Clinical Development, Daiichi Sankyo, Basking Ridge, New Jersey, USA.; Shi M; Biostatistics, Daiichi Sankyo, Basking Ridge, New Jersey, USA.; Miyoshi N; Clinical Development, Daiichi Sankyo, Tokyo, Japan.; Mani V; Department of Radiology, Mount Sinai School of Medicine, New York, New York, USA.; Fayad Z; Department of Radiology, Mount Sinai School of Medicine, New York, New York, USA.; Stephan D; Department of Hypertension, Vascular Disease and Clinical Pharmacology, Strasbourg Regional University Hospital, Strasbourg, France.; Schmidt J; Emergency Department, Clermont-Ferrand University Hospital, Clermont-Ferrand, France; Université Clermont Auvergne, Clermont-Ferrand, France.; Grosso MA; Clinical Development, Daiichi Sankyo, Basking Ridge, New Jersey, USA.; Tapson VF; Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA.; Verhamme P; Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium.; Huisman MV; Department of Medicine-thrombosis and hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
Source
Publisher: Elsevier Country of Publication: England NLM ID: 101170508 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7836 (Electronic) Linking ISSN: 15387836 NLM ISO Abbreviation: J Thromb Haemost Subsets: MEDLINE
Subject
Language
English
Abstract
Background: The optimal treatment of intermediate-risk pulmonary embolism (PE) in hemodynamically stable patients remains unknown. Fibrinolytics reduce the risk of hemodynamic deterioration but increase bleeding risk. DS-1040, an inhibitor of thrombin-activatable fibrinolysis inhibitor, enhanced endogenous fibrinolytic activity without increasing bleeding risk in preclinical studies.
Objectives: To evaluate the tolerability and explore the efficacy of DS-1040 in patients with acute PE.
Methods: In this multicenter, randomized, double-blind, placebo-controlled study, ascending doses of intravenous DS-1040 (20-80 mg) or placebo were added to enoxaparin (1 mg/kg twice daily) in patients with intermediate-risk PE. The primary endpoint was the number of patients with major or clinically relevant nonmajor bleeding. The percentage change in thrombus volume and right-to-left ventricular dimensions, assessed using quantitative computed tomography pulmonary angiography, at baseline and after 12 to 72 hours were used to explore the efficacy of DS-1040.
Results: Of 125 patients with all available data, 38 were randomized to placebo and 87 to DS-1040. The primary endpoint occurred in 1 patient in the placebo group (2.6%) and 4 patients who received DS-1040 (4.6%). One subject experienced major bleeding (DS-1040 80 mg group); no fatal or intracranial bleeding occurred. Thrombus volume was 25% to 45% lower after infusion, with no differences between the DS-1040 and placebo groups. There was no difference in the change from baseline right-to-left ventricular dimensions between the DS-1040 and placebo groups.
Conclusion: In patients with acute PE, adding DS-1040 to standard anticoagulation was not associated with an increase in bleeding but did not improve thrombus resolution or right ventricular dilation.
(Copyright © 2023 International Society on Thrombosis and Haemostasis. All rights reserved.)
Objectives: To evaluate the tolerability and explore the efficacy of DS-1040 in patients with acute PE.
Methods: In this multicenter, randomized, double-blind, placebo-controlled study, ascending doses of intravenous DS-1040 (20-80 mg) or placebo were added to enoxaparin (1 mg/kg twice daily) in patients with intermediate-risk PE. The primary endpoint was the number of patients with major or clinically relevant nonmajor bleeding. The percentage change in thrombus volume and right-to-left ventricular dimensions, assessed using quantitative computed tomography pulmonary angiography, at baseline and after 12 to 72 hours were used to explore the efficacy of DS-1040.
Results: Of 125 patients with all available data, 38 were randomized to placebo and 87 to DS-1040. The primary endpoint occurred in 1 patient in the placebo group (2.6%) and 4 patients who received DS-1040 (4.6%). One subject experienced major bleeding (DS-1040 80 mg group); no fatal or intracranial bleeding occurred. Thrombus volume was 25% to 45% lower after infusion, with no differences between the DS-1040 and placebo groups. There was no difference in the change from baseline right-to-left ventricular dimensions between the DS-1040 and placebo groups.
Conclusion: In patients with acute PE, adding DS-1040 to standard anticoagulation was not associated with an increase in bleeding but did not improve thrombus resolution or right ventricular dilation.
(Copyright © 2023 International Society on Thrombosis and Haemostasis. All rights reserved.)