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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(05): 857-866
DOI: 10.1055/a-1653-4699
Trial Protocol Design Paper

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate–High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial

Olivier Sanchez
1   AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France
2   INSERM UMR S 1140 Innovative Therapies in Hemostasis, Paris, France
3   Université de Paris, Paris, France
4   FCRIN INNOVTE, St-Etienne, France
,
Anaïs Charles-Nelson
5   AP-HP, hôpital européen Georges-Pompidou, Unité de Recherche Clinique, APHP.Centre, Paris, France
6   INSERM, Centre d'Investigation Clinique 1418 (CIC1418) Épidémiologie Clinique, Paris, France
,
Walter Ageno
7   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Stefano Barco 
8   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
9   Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland
,
Harald Binder
10   Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
,
Gilles Chatellier
3   Université de Paris, Paris, France
5   AP-HP, hôpital européen Georges-Pompidou, Unité de Recherche Clinique, APHP.Centre, Paris, France
6   INSERM, Centre d'Investigation Clinique 1418 (CIC1418) Épidémiologie Clinique, Paris, France
,
Daniel Duerschmied
11   Department of Cardiology and Angiology I, University Heart Center Freiburg - Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Klaus Empen
12   Department of Internal Medicine, Städtisches Klinikum Dessau, Germany
,
Melanie Ferreira
13   Internal Medicine Department, Hospital Garcia de Orta, Almada, Portugal
,
Philippe Girard
4   FCRIN INNOVTE, St-Etienne, France
14   Département Thoracique, Institut Mutualiste Montsouris, Paris, France
,
Menno V. Huisman
15   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Dutch Thrombosis Network, Leiden, The Netherlands
,
David Jiménez
16   Department of Respiratory Diseases, Ramon y Cajal Hospital, Universidad de Alcalá (IRYCIS), CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain
,
Sandrine Katsahian
3   Université de Paris, Paris, France
5   AP-HP, hôpital européen Georges-Pompidou, Unité de Recherche Clinique, APHP.Centre, Paris, France
6   INSERM, Centre d'Investigation Clinique 1418 (CIC1418) Épidémiologie Clinique, Paris, France
17   INSERM UMR_S 1138 équipe 22, Centre de Recherche des Cordeliers, Paris, France
,
Matija Kozak
18   Department of Vascular Diseases, University Medical Center, Ljubljana, Slovenia
,
Mareike Lankeit
8   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
19   Department of Internal Medicine, Vascular Medicine and Haemostaseology, Vivantes Klinikum im Friedrichshain, Berlin, Germany
20   Clinic of Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany
,
Nicolas Meneveau
4   FCRIN INNOVTE, St-Etienne, France
21   Department of Cardiology, University Hospital Jean Minjoz, Besançon, France
22   EA3920, University of Burgundy Franche-Comté, Besançon, France
,
Piotr Pruszczyk
23   Department of Internal Medicine and Cardiology, Medical University of Warsaw, Warsaw, Poland
,
Antoniu Petris
24   Grigore T. Popa University of Medicine and Pharmacy Iasi, Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, Iasi, Romania
,
Marc Righini
25   Division of Angiology and Haemostasis, Geneva University Hospital, University of Geneva, Geneva, Switzerland
,
Stephan Rosenkranz
26   Department III of Internal Medicine and Cologne Cardiovascular Research Center (CCRC), Cologne University Heart Center, Cologne, Germany
,
Sebastian Schellong
27   Department of Internal Medicine 2, Municipal Hospital Dresden, Dresden, Germany
,
Branislav Stefanovic
28   Cardiology Clinic, Emergency Center, University Clinical Center of Serbia, School of Medicine University Belgrade, Belgrade, Serbia
,
Peter Verhamme 
29   Vascular Medicine and Haemostasis, Department of Cardiovascular Medicine, University Hospitals Leuven, Leuven, Belgium
,
Kerstin de Wit
30   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Eric Vicaut
31   AP-HP, Unité de Recherche Clinique St-Louis-Lariboisière, Université Denis Diderot, Paris, France
,
Andreas Zirlik
32   Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
,
Stavros V. Konstantinides 
8   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
33   Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
,
Guy Meyer   †
1   AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France
3   Université de Paris, Paris, France
4   FCRIN INNOVTE, St-Etienne, France
,
for the PEITHO-3 Investigators › Author Affiliations Funding The work of Stavros Konstantinides was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503). The authors are responsible for the contents of this publication.
PEITHO-3 is an independent, investigator-initiated trial. The study is being supported by public funding, specifically by grants from the French Ministry of Health (PHRCN-16–0580), the German Research Foundation (Deutsche Forschungsgemeinschaft; KO 1939/3–1), the Canadian Institutes of Health Research and the Spanish Ministry of Science and Innovation. In addition, the sponsor, Assistance Publique – Hôpitaux de Paris, has obtained the study drug and a grant from the market authorization holder of alteplase, Boehringer Ingelheim. The authors are solely responsible for the design and conduct of the trial, for all study analyses, and for the drafting and editing of reports and publications and their final contents.
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Abstract

Intermediate–high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate–high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.

Keywords

pulmonary embolism - intermediate–high-risk - reduced-dose thrombolysis - prognosis - randomized trial

† Deceased.




Publication History

Received: 22 June 2021

Accepted: 28 July 2021

Accepted Manuscript online:
24 September 2021

Article published online:
31 October 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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