Low Dosage of rt-PA in the Treatment of Pulmonary Thromboembolism in China

• The improvement of the right hart function on echocardiograms [ Time Frame: within the 1st 14 days ] [ Designated as safety issue: No ]
• Perfusion defect score of lung V/Q scans [ Time Frame: within the 1st 14 days ] [ Designated as safety issue: No ]
• Quantitative computed tomographic pulmonary angiography (CTPA) score on 2d, 14d after treatment. [ Time Frame: within the 1st 14 days ] [ Designated as safety issue: No ]

• Major or minor bleeding [ Time Frame: within 1st 14 days ] [ Designated as safety issue: Yes ]
• PE recurrence [ Time Frame: within the 1st 14 days ] [ Designated as safety issue: Yes ]
• Death [ Time Frame: within the 1st 14 days ] [ Designated as safety issue: Yes ]

Recombinant tissue plasminogen activator (rt-PA) is currently the most commonly used thrombolytic drug in patients with pulmonary thromboembolism (PTE). Optimal dosing with maximal benefits and minimal risks is of great importance. Considering the lower body weight in general Chinese population, we compared the efficacy and safety of lower dose rt-PA 50mg/2h regimen with the FDA-approved rt-PA 100mg/2h regimen in selected PTE patients.

Pulmonary thromboembolism (PTE) is a severe and common clinical problem with substantial morbidity and mortality both in US and in Europe. Used to be considered as a rare disease in China, PTE has been increasingly diagnosed in recent years due to the increased awareness and the improvement of imaging techniques. PTE is life threatening without proper intervention at the early onset. Effective treatment can decrease the mortality and the complication of chronic thromboembolic pulmonary hypertension (CTEPH).

Recombinant tissue-type plasminogen activator (rt-PA) is currently the most commonly used drug for PTE thrombolysis. Like most thrombolytic medications, rt-PA carries a risk of significant bleeding, which is dose dependent. Thus, optimal dosing that can maximize benefits and minimize risks is of great importance. There is substantial controversy and debate regarding the optimal rt-PA dosage for thrombolytic therapy and whether the same dose should be used in all patients. Low dose of intravenous rt-PA for thrombolysis after acute myocardial infarction (AMI) had been suggested by previous studies. Experimental and clinical studies have indicated that a lower dose of rt-PA bolus may be potentially safer, and yet equally effective then the 2-h 100 mg rt-PA continuous infusion for PTE.

Considering lower body weight in Chinese population, a lower dose of 50mg rt-PA/2h may exhibit similar efficacy and safety as 100mg/2-h rt-PA for treating acute PTE in this population. We, therefore, compared these two regimens in a multi-center, randomized, controlled trial. The efficacy was assessed by the improvement of the right ventricular function on echocardiograms, perfusion defect score of lung V/Q scans or quantitative computed tomographic (CT) evaluation, safety was evaluated by incidence of major or minor bleeding, death rate, and PTE recurrence on 24h,14d after treatment.

110 patients will be randomized in the study. The patients included in the study will be randomized, in a double blind fashion, to receive rt-PA 100mg 2h (55 patients) or rt-PA50mg 2h(55 patients).Study treatment should be administered within 72 hours from echocardiography. Echocardiography will be repeated at 24 hours and 14 days from rt-PA injection. A Follow-up visit at 14 days from randomization will include: clinical history, physical examination and ECG and an echocardiographic examination CTPA and V/Q scan.

• Pulmonary Embolism
• Thromboembolism

• Drug: rt-PA
  rt-PA 100 mg continuous intravenous infusion for 2 hours
  Other Name: Recombinant tissue plasminogen activator
• Drug: rt-PA
  rt-PA 50 mg continuous intravenous infusion for 2 hours
  Other Name: Recombinant tissue plasminogen activator

• Active Comparator: Group 1
  rt-PA 100 mg continuous intravenous infusion for 2 hours
  Intervention: Drug: rt-PA
• Experimental: group 2
  rt-PA 50 mg continuous intravenous infusion for 2 hours
  Intervention: Drug: rt-PA

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Inclusion Criteria:

• age between 18 and 75
• symptomatic PE confirmed by: a high probability ventilation-perfusion lung scanning (V/Q scan) or the presence of intraluminal filling defect on spiral computed tomographic pulmonary angiography (CTPA)
• PTE patients with haemodynamic instability, or cardiogenic shock
• anatomic obstruction more than 2 lobes on CTPA, or defect more than 7 segments on V/Q scan combined with evidence of right ventricular dysfunction(RVD) and pulmonary hypertension on echocardiography
• written informed consent

Exclusion Criteria:

• active bleeding or spontaneous intracranial hemorrhage
• major surgery, organ biopsy or recent puncture of a non-compressible vessel less than 10 days
• cerebral arterial thrombosis within 2 months
• gastro-intestinal bleeding within 10 days
• major trauma within the past 15 days
• neurosurgery or ophthalmologic operation with 30 days
• uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg)
• recent external cardiac resuscitation manoeuvres
• platelet count < 100 000/mm3 at admission
• pregnancy, puerperium or lactation with 2 weeks
• infectious pericarditis or endocarditis
• severe hepatic and kidney dysfunction
• hemorrhagic retinopathy due to diabetes
• a known bleeding disorder