Reduced Dose Thrombolytic in Intermediate/High Risk Pulmonary Thromboembolism

Treatment Approach in Patients Diagnosed With Pulmonary Thromboembolism With Intermediate-High Risk Interms of Early Mortality After the Establisment of Ege Pulmonary Embolism Team

Pulmonary Embolism(PE) requires multidisciplinary approach as a highly morbid and mortal disease. This multidisciplinary approach creates clinical benefits in diagnostic and therapeutic process. And these benefits are pointed out in certain studies and guidelines. For these reasons, a Pulmonary Embolism Response Team (PERT) was established on 5 th November 2018 which is called as Ege Pulmonary Embolism Team (EGEPET) in our university.

In recent years, it is stated that the carefully use of thrombolytic in patients with intermediate-high risk PE based on early mortality classification. Some studies have reported that the use of thrombolytic may cause clinical benefits. But which used drug and which dose are not defined clearly yet.

After establishment of EGEPET, the investigators observed that patients with intermediate-high risk PE more receive reduced dose thrombolytic than the pre-EGEPET period. And the investigators aimed to compare treatment changes after and before the establishment of EGEPET. Also, the investigator will compare initial reduced dose thrombolytic therapy after EGEPET with initial anticoagulation therapy before EGEPET (historical group) in terms of mortality and complication.

As the reduced dose thrombolytic, Alteplase 50 mg is used in our hospital. Low-molecular weight heparin (LMWH), standard heparin and rarely Fondaparinux are used for anticoagulation therapy. Low-molecular weight heparin is generally applied for treatment, in case there is no contraindication.

Our primary end-point is to assess 30-day mortality and secondary-end points are to detect in one year-mortality and complications. The investigators will compare the mortality and complication rates in these groups.

N0 hypothesis; In the intermediate-high risk group diagnosed with PE, there is an increased mortality rate in the patients treated with half-dose thrombolytic (Alteplase 50 mg) than our historical group or the literature.

N1 hypothesis; In the intermediate-high risk group diagnosed with PE, there is no an increased mortality rate in the patients treated with half-dose thrombolytic (Alteplase 50 mg) than our historical group or the literature.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Embolism
• Intervention / Treatment: Drug: Tissue Plasminogen Activator, Alteplase; Drug: Low-molecular weight heparin

Detailed Description

Pulmonary thromboembolism ranks 3rd among cardiovascular diseases in terms of mortality. Pulmonary Embolism (PE) is a challenging disease that requires rapid approach both in the diagnosis and treatment process. Due to the challenging nature of the disease, Pulmonary Embolism Response Teams (PERT) have emerged for quick intervention in patients with PE. In the management of PE, multidisciplinary approach that includes the branches of pulmonary diseases, cardiology, emergency medicine, cardiovascular surgery, anesthesiology and radiology provides clinical advantages. Therefore, a PERT was established and called Ege Pulmonary Embolism Team (EGEPET). EGEPET established on 5th of November 2018. This team contains specialists from Pulmonary Diseases, Cardiology, Emergency Medicine, Cardiovascular Surgery, Anesthesiology and Radiology Departments. EGEPET works during 7/24 as a response team. It has been stated in recent publications and pulmonary thromboembolism guidelines that the establishment of multidisciplinary study group which is similar to our group will be more effective in the diagnosis, treatment and follow-up processes of PE patients.

Specially, there are some different opinions for the treatment of Intermediate-High risk based on according to early mortality with PE patients. While some guidelines suggest initial anticoagulation treatment without thrombolytic treatment, some researchers state that thrombolytic treatment can be used in Intermediate-High risk patients. These researchers indicate that the careful use of thrombolytic can be improved in clinical situation of PE patients. The careful usage is meant to use reduced dose thrombolytic and to follow up the patients closely for bleeding complication.

In cases diagnosed with intermediate-high risk PE in related to early mortality, it has been seen that half-dose thrombolytics are given mostly in our daily life practice after EGEPET.

So, the investigators planned to evaluate the mortality and morbidity rates in the patients who were diagnosed with pulmonary thromboembolism with intermediate-high risk in terms of early mortality and who received half-dose thrombolytics according to the result of the EGEPET consultation.

50 mg Alteplase is used as thrombolytic treatment and, low-molecular weight heparin (LMWH), standard heparin and rarely Fondaparinux are used for initial anticoagulation treatment. Low-molecular weight heparin is generally applied for treatment, in case there is no contraindication.

This study is an observational drug study. Researchers of this study did not and will not intervene the treatment of patients. Treatment decision of the patients is decided by EGEPET physicians.

The investigators will compare the patients diagnosed with intermediate-high risk PE who received reduced dose thrombolytic which the decision is made by EGEPET with the other patients who did not get thrombolytic treatment in terms of mortality and morbidity.

The other patient group with intermediate-high risk PE will be created from our historical data to prevent to selection bias. Because, EGEPET offers generally reduced dose thrombolytic in intermediate-high risk PE patients. Otherwise, patients having high bleeding scores (e.g. RIETE bleeding score), multiple and severe comorbidities or patients who are quite old generally receive only anticoagulation treatment.

The patients assessed our study were classed into three groups. All of the patients have PE and are stated into intermediate-high risk according to early mortality.

First group is prospective group, which contains patients recruited after approval of ethic committee of this study. Ethic committee was taken from both organization Ege University and The Ministry of Health-Türkiye.

Second group is retrospective group, which contains patients evaluated by EGEPET and received reduced dose thrombolytic treatment.

Third group is called as historical control group. This patients group were diagnosed and treated with anticoagulants not thrombolytic treatment before establishment of EGEPET.

First and second groups compose the thrombolytic group, third group create the anticoagulant group (control)

The investigators are going to collect data (clinical, laboratory and radiological variables) of these patients to get detailed clinical information.

The investigators will compare the thrombolytic group with anticoagulant group (control). The primary end-point is to evaluate 30-day mortality and secondary-end point are to detect in one year-mortality and complications.

The investigators will compare mortality and complication rates in both groups.

N0 hypothesis; In the intermediate-high risk group diagnosed with PE, there is an increased mortality rate in the patients treated with half-dose thrombolytic (Alteplase 50 mg) than our historical group or the literature.

N1 hypothesis; In the intermediate-high risk group diagnosed with PE, there is no an increased mortality rate in the patients treated with half-dose thrombolytic (Alteplase 50 mg) than our historical group or the literature.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

Study Locations

• Turkey
  • Bornova/İzmir
    • İzmir, Bornova/İzmir, Turkey, 35100
      • Recruiting
      • Ege University
      • Contact: Pervin KORKMAZ, MD; Phone Number: +902323902900; Email: pervinkorkmaz@yahoo.com
      • Contact: Ömer Selim UNAT, MD; Phone Number: +902323902900; Email: unatomerselim@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

In this study, intermediate-high risk PE patients will divide whether receice thrombolytic treatment or not. And two group are going to compare in the context of mortality rate. We anticipate that 50 patients should be enough for statistically powerful study. We predict this number according to previous studies and power analyses.

Description

Inclusion Criteria:

• Patients which are in intermediate-high risk class ased on mortality in the ESC/ERS Pulmonary Embolism Risk Classification

Exclusion Criteria:

• Unwillingness of patient to participate in the study
• The case is in the intermediate-high risk class, but there is an unstable disease that will affect mortality due to malignancy or general medical condition.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Thrombolytic Treatment Group; These are the patients with intermediate-high riskPE and consulted by EGEPET. They received reduced dose thrombolytic treatment.	Drug: Tissue Plasminogen Activator, Alteplase; Reduced dose (50 mg) Alteplase is used for the patients in the thrombolytic treatment group.
Anticoagulation Treatment Group; This group includes patients who diagnosed wit PE before the establishment of EGEPET. And these patients are classed into intermediate-high risk based on early mortality and received anticoagulation treatment, not thrombolytic treatment.	Drug: Low-molecular weight heparin; Patients in the anticoagulation treatment group receive this treatment and do not receive thrombolytic treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30 day Mortality	Includes 30-day mortality and contains all causes of death.	30 day after diagnosis of pulmonary tromboembolism

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1 year Mortality	Includes 1 year mortality and contains all causes of death.	1 year after diagnosis of pulmonary tromboembolism

Collaborators and Investigators

• Sponsor: Ege University

Publications and helpful links

General Publications

• Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; "MOPETT" Investigators. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7. doi: 10.1016/j.amjcard.2012.09.027. Epub 2012 Oct 24.
• 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.
• Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ni Ainle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020 Jan 21;41(4):543-603. doi: 10.1093/eurheartj/ehz405. No abstract available.
• Mirambeaux R, Leon F, Bikdeli B, Morillo R, Barrios D, Mercedes E, Moores L, Tapson V, Yusen RD, Jimenez D. Intermediate-High Risk Pulmonary Embolism. TH Open. 2019 Dec 4;3(4):e356-e363. doi: 10.1055/s-0039-3401003. eCollection 2019 Oct.
• Wendelboe AM, Raskob GE. Global Burden of Thrombosis: Epidemiologic Aspects. Circ Res. 2016 Apr 29;118(9):1340-7. doi: 10.1161/CIRCRESAHA.115.306841.

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2022
• Primary Completion (Anticipated): June 3, 2023
• Study Completion (Anticipated): June 3, 2024

Study Registration Dates

• First Submitted: August 22, 2022
• First Submitted That Met QC Criteria: August 22, 2022
• First Posted (Actual): August 23, 2022

Study Record Updates

• Last Update Posted (Actual): September 1, 2022
• Last Update Submitted That Met QC Criteria: August 29, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Mortality; Complication; Pulmonary Embolism; Pulmonary Embolism Response Teams; Thrombolytic Treatment; Anticoagulation Treatment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thromboembolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Tissue Plasminogen Activator; Plasminogen
• Other Study ID Numbers: 21-AKD-107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No