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

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

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).

Study Overview

• Status: Unknown
• Conditions: Pulmonary Embolism; Pulmonary Thromboembolisms
• Intervention / Treatment: Drug: Recombinant tissue plasminogen activator (rt-PA); Drug: Low Molecular Weight Heparin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 460
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Chen Wang, PhD,MD; Phone Number: 8610-85231893; Email: cyh-birm@263.net
• Study Contact Backup: Name: Tuguang Kuang, PhD,MD; Phone Number: 8610-85231451; Email: ktg2004@sina.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Recruiting
      • Beijing Daxing People's Hospital
      • Contact: Yongxiang Zhang, MD
      • Principal Investigator: Yongxiang Zhang, MD
    • Beijing, Beijing, China
      • Recruiting
      • Beijing Fuwai Hospital
      • Contact: Zhihong Liu, MD
      • Principal Investigator: Zhihong Liu, MD
    • Beijing, Beijing, China
      • Not yet recruiting
      • Beijing Hospital, Ministry of Health
      • Contact: Baomin Fang, MD
      • Principal Investigator: Baoming Fang, MD
    • Bejing, Beijing, China, 100020
      • Recruiting
      • Beijing Chao Yang Hospial
      • Contact: Yuanhua Yang, PhD,MD; Phone Number: 8610-65060167; Email: yyh1031@sina.com
      • Principal Investigator: Chen Wang, PhD,MD
      • Sub-Investigator: Yuanhua Yang, PhD,MD
  • GUang Dong
    • Guang Zhou, GUang Dong, China
      • Recruiting
      • The Third Affiliated Hospital of Zhongshan University in Guangzhou
      • Contact: yulin Zhou, MD
      • Principal Investigator: Tiantuo Zhang, MD
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • The First Affiliated Hospital of Zhongshan University in Guangzhou
      • Contact: Mian Zeng, MD
      • Principal Investigator: Canmao Xie, MD
  • Guangxi
    • Nan ning, Guangxi, China
      • Recruiting
      • The Guangxi Zhuang Autonomous Region people's Hospital
      • Contact: shengze Long, MD
      • Principal Investigator: Zhiqiang Qing, PhD,MD
  • Guangzhou
    • Shenzhen, Guangzhou, China
      • Recruiting
      • Guangzhou Shenzhen People's Hospital
      • Contact: Chen Qiu, MD
      • Principal Investigator: Chen Qiu, MD
  • Hebei
    • Chengde, Hebei, China
      • Recruiting
      • Affiliated Hospital of Chengde Medical College
      • Principal Investigator: Qing Zhang, MD
      • Contact: Guifang Pang, MD
    • Handan, Hebei, China
      • Recruiting
      • The first hospital of Handan city Hebei Province
      • Contact: Jinghui Ye, MD
      • Principal Investigator: Jinghui Ye, MD
    • Hengshui, Hebei, China
      • Recruiting
      • Hebei Hengshui international Heping Hospital
      • Contact: Zhaobo Cui, MD
      • Principal Investigator: Zhaobo Cui, MD
    • Shijiazhuang, Hebei, China
      • Recruiting
      • Hebei Affiliated Hospital of North China Coal Medical University
      • Contact: Baibing Liu, MD
      • Principal Investigator: Hongyang Wang, MD
    • Shijiazhuang, Hebei, China
      • Recruiting
      • Hebei Medical University Second Hospital
      • Contact: Yadong Yuan, MD
      • Principal Investigator: Yadong Yuan, MD
  • Heilongjiang
    • Harbin, Heilongjiang, China
      • Recruiting
      • No.2 Affiliated Hospital of Harbin Medical University
      • Contact: Hong Chen, MD
      • Principal Investigator: Hong Chen, MD
  • Inner Mongolia
    • Baotou, Inner Mongolia, China
      • Recruiting
      • The Third Affiliated Hospital of Inner Mongolia Medical College
      • Contact: Ling Wang, MD
      • Principal Investigator: Jingping Yang, MD
    • Hohhot, Inner Mongolia, China
      • Recruiting
      • Hospital of Inner Mongolia Autonomous Region
      • Contact: Weilie Wang, MD
      • Principal Investigator: Wenting Zhang, MD
  • Liaoning
    • Anshan, Liaoning, China
      • Recruiting
      • Anshan Iron and Steel Company General Hospital
      • Contact: Hongyu Zhou, MD
      • Principal Investigator: Hongyu Zhou, MD
    • Dalian, Liaoning, China
      • Recruiting
      • The First Hospital of Dalian Medical University
      • Contact: Yingqun Ji, MD
      • Principal Investigator: Zhonghe Zhang, MD
    • Shenyang, Liaoning, China
      • Recruiting
      • Liaoning General Hospital of Shenyang Military Region
      • Contact: Liang Shi, MD
      • Principal Investigator: Zhuang Ma, MD
    • Shenyang, Liaoning, China
      • Recruiting
      • Shenyang Medical College affiliated Fengtian Hospital
      • Contact: Shuyue Xia, MD
      • Principal Investigator: Shuyue Xia, MD
  • Ningxia
    • Yinchuan, Ningxia, China
      • Recruiting
      • Affiliated Hospital of Ningxia Medical University
      • Contact: Zheng Yang, MD
      • Principal Investigator: Jin Zhang, MD
  • Shandong
    • Jining, Shandong, China
      • Recruiting
      • Shandong Jining Medical University Affiliated Hospital
      • Contact: Luning Jiang, MD
      • Principal Investigator: Luning Jiang, MD
    • Qingdao, Shandong, China
      • Recruiting
      • Shandong Medical College Affiliated Hospital of Qiingdao University
      • Contact: Li Tong, MD
      • Principal Investigator: Zhaozhong Cheng, MD
    • Yantai, Shandong, China
      • Recruiting
      • Shandong Yantai city Yantai Mountain hospital
      • Contact: Lijun Kang, MD
      • Principal Investigator: Shudong Zhang, MD
  • Shanghai
    • Shanghai, Shanghai, China
      • Recruiting
      • Ruijin Hospital Affiliated to Shanghai Jiao Tong University
      • Contact: Guochao Shi, MD
      • Principal Investigator: Shaoguang Huang, MD
    • Shanghai, Shanghai, China
      • Recruiting
      • Second Military Medical University Changhai Hospital
      • Contact: Wei Zhang, MD
      • Principal Investigator: Qiang Li, MD
    • Shanghai, Shanghai, China
      • Recruiting
      • Zhongshan Hospital Affiliated to Shanghai Fudan University
      • Contact: Jinjun Jiang, MD
      • Principal Investigator: Chunxue Bai, PhD,MD
  • Shanxi
    • Taiyuan, Shanxi, China
      • Recruiting
      • Shanxi Medical University Second Hospital
      • Contact: Xu Wang, MD
      • Principal Investigator: Zhuola Liu, MD
    • Taiyuan, Shanxi, China
      • Recruiting
      • The First Hospital of Shanxi Medical University
      • Contact: Xiaoyun Hu, MD
      • Principal Investigator: Yongcheng Du, MD
    • Xi'an, Shanxi, China
      • Recruiting
      • The Fourth military medical university, Xijing Hospital
      • Contact: Shengqing Li, PhD, MD
      • Principal Investigator: Changgui Wu, MD
  • Sichuan
    • Chengdu, Sichuan, China
      • Recruiting
      • Sichuan University, West China Hospital
      • Contact: Qun Yi, MD
      • Principal Investigator: Qun Yi, MD
  • Xinjiang
    • Urumqi, Xinjiang, China
      • Recruiting
      • The First Hospital of Xinjiang Medical University
      • Contact: Zaiyi Wang, MD
      • Principal Investigator: Zaiyi Wang, MD
    • Urumqi, Xinjiang, China
      • Recruiting
      • The Xinjiang Uygur Autonomous Region people's Hospital
      • Contact: Ying Chen, MD
      • Principal Investigator: Xiaohong Yang, MD
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • Zhejiang Sir Run Run Shaw Hospital
      • Contact: Guofeng Ma, MD
      • Principal Investigator: Kejing Ying, MD
    • Wenzhou, Zhejiang, China
      • Recruiting
      • The First Affiliated Hospital of Wenzhou Medical College in Zhejiang
      • Contact: Yupeng Xie, MD
      • Principal Investigator: Liangxing Wang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 y≤Age≤75y
2. 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
3. Hemodynamic stability, diastolic pressure>90mmHg.

4. 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:

1. RV anterior wall thickness > 5mm confirmed by echocardiography
2. Active internal bleeding and spontaneous intracranial hemorrhage in preceding 6 months
3. Major surgery, organ biopsy or non-compressible punctures within 2 weeks
4. Ischemic stroke occurred within 2 months
5. Gastrointestinal bleeding within 10 days
6. Severe trauma occurred within15 days
7. Neurosurgery or eye surgery within 1 months
8. Severe hypertension difficult to control (systolic blood pressure>180mmHg or diastolic blood pressure>110mmHg)
9. Cardiopulmonary resuscitation
10. Platelet count less than 100×109 / L
11. Pregnancy, or within 2 week post partum
12. Infective endocarditis; left atrial thrombus; aneurysm
13. Serious liver and kidney dysfunction
14. Diabetic hemorrhagic retinopathy
15. Suffering with bleeding disorders
16. Chronic thromboembolic pulmonary hypertension
17. Moderate to severe chronic obstructive pulmonary disease (COPD).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Beijing Chao Yang Hospital
• Collaborators: Ministry of Science and Technology of the People´s Republic of China
• Investigators: Principal Investigator: Chen Wang, PhD,MD, Beijing Chao Yang Hospital

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Anticipated): July 1, 2012
• Study Completion (Anticipated): December 1, 2012

Study Registration Dates

• First Submitted: February 9, 2012
• First Submitted That Met QC Criteria: February 10, 2012
• First Posted (Estimate): February 13, 2012

Study Record Updates

• Last Update Posted (Estimate): February 14, 2012
• Last Update Submitted That Met QC Criteria: February 11, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Heparin; pulmonary embolism; Thrombolysis; right ventricular dysfunction
• 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; Nadroparin
• Other Study ID Numbers: BJCYH1893