Low Dose Rt-PA for Acute Normotensive Pulmonary Embolism With RVD

Study Overview
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Brief Summary
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In selected patients with acute pulmonary embolism(PE), low dose (50mg/2h) recombinant tissue plasminogen activator (rt-PA) regimen had been reported to have less bleeding tendency than the FDA-approved rt-PA 100mg/2h regimen 100mg/2h regimen (3% vs.10%), it is worthwhile to reveal whether low dose rt-PA plus low molecular weight heparin (LMWH) can rapidly reverses RV pressure overload in PE, but not increase bleeding and other adverse events. The aim of the study is to compare thrombolytic treatment with LMWH in patients with acute normotensive PE with right ventricular dysfunction(RVD).

Detailed Description
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In acute pulmonary embolism (PE), normotensive patients with acute RV dysfunction on echocardiography or computed tomography and with myocardial troponin elevation may have an adverse outcome. Thrombolysis rapidly reverses RV pressure overload in PE, but it increases the possibility of bleeding and it remains unclear whether it may improve the early or long-term clinical outcome of these selected normotensive patients. In our previous study, we found that low dose (50mg/2h) recombinant tissue plasminogen activator (rt-PA) regimen had less bleeding tendency than the 100mg/2h regimen (3% vs.10%), it is worthwhile to reveal whether low dose rt-PA plus Low Molecular Weight Heparin (LMWH) can rapidly reverses RV pressure overload in PE, but not increase bleeding and other adverse events. In this prospective, multicenter, randomized, control study, we compare low dose rt-PA plus LMWH vs. LMWH alone in acute normotensive pulmonary embolism patients with RV dysfunction. The primary efficacy outcome is the composite of death from any cause or treatment failure, improvements of right ventricular functions on echocardiogram and pulmonary artery obstruction on CT angiographs within 7 days of randomization. Second efficacy outcome is the recurrence of pulmonary embolism and deep venous thrombosis. Safety outcomes include serious life threatening bleeding such as cerebral hemorrhage and other major bleeding episodes, also include mild bleeding. In addition, 90-day clinical and echocardiographic follow-up will be performed, the recurrence of pulmonary embolism and deep venous thrombosis will be recorded. The study is expected to enroll approximately 460 patients. By determining the benefits vs risks of Low dose rt-PA plus LMWH compared with LMWH alone for the treatment in submassive or intermediate-risk PE, this trial is expected to reveal the worth of Low dose rt-PA plus LMWH treatment and what kind of PE patients are suitable for thrombolysis.

Official Title
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Low Dose Rt-PA Plus LMWH Compared With LMWH Alone for the Treatment of Normotensive Pulmonary Embolism Patients With Acute RV Dysfunction: A Randomized，Multi-Center，Controlled Trial

Conditions
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Pulmonary Thromboembolisms, Pulmonary Embolism

Intervention / Treatment
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* Drug: Recombinant tissue plasminogen activator (rt-PA)
* Drug: Low Molecular Weight Heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 y≤Age≤75y Acute PE (first symptoms occurred 14 d or less before randomization) confirmed by lung scan, or a positive computed tomographic pulmonary angiogram, or a positive selective pulmonary angiogram Hemodynamic stability, diastolic pressure>90mmHg. RV dysfunction confirmed by echocardiography (≥1 criterion), except left-side heart disease, congenital heart disease and mitral valve disease. Increase of the right ventricle showed presented with RV end-diastolic anteroposterior diameter >25 mm, Right/left ventricular end-diastolic diameter >1 (apical or subcostal 4-chamber view) or Right/left ventricular end-diastolic anteroposterior diameter >0.5 Hypokinesis of RV-free wall (range of motion less than 5 mm) Tricuspid regurgitation pressure >30mmHg Exclusion Criteria: RV anterior wall thickness > 5mm confirmed by echocardiography Active internal bleeding and spontaneous intracranial hemorrhage in preceding 6 months Major surgery, organ biopsy or non-compressible punctures within 2 weeks Ischemic stroke occurred within 2 months Gastrointestinal bleeding within 10 days Severe trauma occurred within15 days Neurosurgery or eye surgery within 1 months Severe hypertension difficult to control (systolic blood pressure>180mmHg or diastolic blood pressure>110mmHg) Cardiopulmonary resuscitation Platelet count less than 100×109 / L Pregnancy, or within 2 week post partum Infective endocarditis; left atrial thrombus; aneurysm Serious liver and kidney dysfunction Diabetic hemorrhagic retinopathy Suffering with bleeding disorders Chronic thromboembolic pulmonary hypertension Moderate to severe chronic obstructive pulmonary disease (COPD).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose (50mg/2h) rt-PA plus LMWH<br>Low dose (50mg/2h) recombinant tissue plasminogen activator (rt-PA) plus low molecular weight heparin(LMWH)regimen | Drug: Recombinant tissue plasminogen activator (rt-PA)<br>* Low dose (50mg/2h) rt-PA plus LMWH<br>* Other names: rt-PA;|
| Active Comparator: LMWH<br>Low molecular weight heparin | Drug: Low Molecular Weight Heparin<br>* 0.1ml/10kg,q12h,5-7 days<br>* Other names: Nadroparin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the composite end point of death from any cause or treatment failure,recurrence of VTE |  | 7 days | 
| improvements of right ventricular functions on echocardiogram and pulmonary artery obstruction on CT angiographs |  | 7 days | 
| serious life threatening bleeding such as cerebral hemorrhage and other major bleeding episodes |  | 7 days | 
| clinical relevant non-major bleedings |  | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the composite end point of death from any cause or treatment failure,recurrence of VTE |  | 3 months and 6 months | 
| improvements of right ventricular functions on echocardiogram and pulmonary artery obstruction on CT angiographs |  | 3 months and 6 months | 
| serious life threatening bleeding such as cerebral hemorrhage and other major bleeding episodes |  | 3 months and 6 months | 
| clinical relevant non-major bleedings |  | 3 months and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary embolism, right ventricular dysfunction, Thrombolysis, Heparin