Clinical trial NCT00639743: PEITHO Pulmonary Embolism Thrombolysis Study
Official title: Comparison Trial Evaluating Efficacy and Safety of Single i.v. Bolus Tenecteplase Plus Standard Anticoagulation as Compared With Standard Anticoagulation in Normotensive Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Embolism
Keywords: Pulmonary embolism
Heparin
Thrombolytic therapy
Bleeding
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
name: Boehringer Ingelheim
First posted: 2008-03-20
Enrollment: 1005
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Heparin is the reference therapy for most patients with pulmonary embolism. Some patients with sub-massive pulmonary embolism defined by normal blood pressure and dysfunction of the right ventricle have a higher mortality risk. It has been suggested that thrombolytic treatment, a drug that dissolves blood clots more rapidly, may reduce the mortality in those patients. The studies reported to date were unable to confirm or refute this hypothesis because the number of patients included in those studies is too low. The aim of the study is to compare thrombolytic treatment with heparin (which is the reference therapy for pulmonary embolism) in a large group of patients with sub-massive pulmonary embolism.

Detailed description: A prospective, randomized, double-blind, placebo-controlled, international, multicentre, parallel-group comparison trial evaluating the efficacy and safety of single i.v. bolus tenecteplase plus standard anticoagulation as compared with standard anticoagulation in normotensive patients with acute pulmonary embolism and with echocardiographic and laboratory evidence of right ventricular dysfunction.Patients suffering from acute pulmonary embolism (first symptoms occurring within 15 days) confirmed by lung scanning or a positive spiral computed tomogram, or a positive pulmonary angiogram, presenting with right ventricular dysfunction on echocardiography and tested troponin I or T positive will be included in the study if they have no exclusion criteria.Patients in the investigational group will receive: Ø Tenecteplase as a single body-weight (known or estimated) adjusted IV bolus administered over 5 - 10 seconds not later than 30 minutes after randomization, and not later than 2 hours after the diagnosis of RV dysfunction Weight (kg) Dose in mg Dose in units Dose in ml\<60 30 mg 6000 U 6 ml\>60 to \<70 35 mg 7000 U 7 ml\>70 to \<80 40 mg 8000 U 8 ml\>80 to \<90 45 mg 9000 U 9 ml\>90 50 mg 10000 U 10 mlØ and: concomitant therapy-Unfractionated heparin at a dose of 80 IUxKg-1 as an intravenous bolus, followed by an infusion of 18 IUxKg-1xh-1, to be administered immediately after randomization in all patients for at least 48 hours following randomization. Beyond this period, intravenous UFH may be substituted with subcutaneous heparin (LMWH) treatment. The bolus will be omitted when heparin was started before randomisation.Patients in the control group will receive Ø placebo as a single body-weight (known or estimated) adjusted IV bolus administered over 5 - 10 seconds not later than 30 minutes after randomization, and not later than 2 hours after the diagnosis of RV dysfunction. Weight (kg) Dose in ml\<60 6 ml\>60 to \<70 7 ml\>70 to \<80 8 ml\>80 to \<90 9 ml\>90 10 mlØ and concomitant therapy with Unfractionated heparin

Eligibility criteria: Inclusion Criteria:

* Age 18 years or older
* Acute PE (first symptoms occurring 15 days or less before randomisation) confirmed by lung scan, or a positive spiral computed tomogram, or a positive pulmonary angiogram
* Right ventricular dysfunction confirmed by echocardiography or spiral computed tomography of the chest and a positive troponin I or T test

Exclusion criteria:

* Haemodynamic collapse at presentation as defined above
* Known significant bleeding risk
* Administration of thrombolytic agents within the previous 4 days
* Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days
* Uncontrolled hypertension defined as systolic BP \>180 mm Hg and/or diastolic BP \>110 mm Hg at randomisation
* Treatment with an investigational drug under another study protocol in the previous 7 days or greater, according to local requirements
* Previous enrolment in this study
* Known hypersensitivity to tenecteplase, alteplase, unfractionated heparin, or to any of the excipients
* Pregnancy, lactation or parturition within the previous 30 days. Women of childbearing age must have a negative pregnancy test or use a medically accepted method of birth control
* Known coagulation disorder (including vitamin K antagonists)
* Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated

Primary outcomes:
measure: Clinical composite endpoint of all-cause mortality or haemodynamic collapse within 7 days
timeFrame: Day 7
measure: Haemodynamic collapse is defined as: need for cardiopulmonary resuscitation; or systolic blood pressure < 90 mm Hg for at least 15 min or drop of syst
timeFrame: Day 7
Secondary outcomes:
measure: Death within 7 days
timeFrame: Day 7
measure: Haemodynamic collapse within 7 days
timeFrame: Day 7
measure: Confirmed symptomatic pulmonary embolism recurrence within 7 days
timeFrame: Day 7
measure: Death within 30 days
timeFrame: Day 30
measure: Total strokes (intra cranial haemorrhage or ischaemic stroke) within 7 days
timeFrame: Day 7
measure: Major bleeding (other intracranial haemorrhage or ischaemic stroke)
timeFrame: Day 7
Other outcomes:
Locations:
city: Vienne
country: Austria
facility: Vienna Medical University
city: Brussels
country: Belgium
facility: Hospital St. Luc
city: Besançon
country: France
facility: CHU Hopital Jean Minjoz
city: Freiburg
country: Germany
facility: Universistaetsklinik
city: Alexandroupolis
country: Greece
facility: Democritus University of Thrace
city: Pécs
country: Hungary
facility: University of Pécs
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Bologna
country: Italy
facility: Istituto di Cardiologia, Policlinico S.Orsola-MaBologna
city: Warsaw
country: Poland
facility: Medical University of Warsaw
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
city: Ljubljana
country: Slovenia
facility: University Medical Center
city: Madrid
country: Spain
facility: Ramon y Cajal Hospital
Study officials:
affiliation: Assistance Publique Hopitaux de Paris - Department of pneumology - European Hospital George Pompidou - Paris 15
name: Guy MEYER, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Cardiology and Pulmonolog - Universitaetsmedizin Goettingen - 37099 Goettingen, Germany
name: Stavros Konstantinides, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004 Aug 10;110(6):744-9. doi: 10.1161/01.CIR.0000137826.09715.9C. Epub 2004 Jul 19.
citation: Zuo Z, Yue J, Dong BR, Wu T, Liu GJ, Hao Q. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2021 Apr 15;4(4):CD004437. doi: 10.1002/14651858.CD004437.pub6.
citation: Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, Bouvaist H, Couturaud F, Dellas C, Duerschmied D, Empen K, Ferrari E, Galie N, Jimenez D, Kostrubiec M, Kozak M, Kupatt C, Lang IM, Lankeit M, Meneveau N, Palazzini M, Pruszczyk P, Rugolotto M, Salvi A, Sanchez O, Schellong S, Sobkowicz B, Meyer G. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017 Mar 28;69(12):1536-1544. doi: 10.1016/j.jacc.2016.12.039.
citation: Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.
citation: Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012 Jan;163(1):33-38.e1. doi: 10.1016/j.ahj.2011.10.003.