Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism

Article review by Dr Kendrick Law

Clinical Question

In patient’s with intermediate-risk PE does the addition of fibrinolytic therapy to standard anticoagulation therapy improve mortality and/or hemodynamic decompensation in the first 7 days.

Bottom Line

Patient’s with intermediate-risk PE who received fibrinolytic therapy in combination with standard anticoagulation had a statistically significant reduction in hemodynamic instability within 7 days as well as a statistically significant increase in major bleeding events.

Major Points

PE occurs frequently and can be a cause of significant morbidity and mortality. In patient’s with high risk PE (PE + hemodynamic instability) immediate advanced therapy is warranted including consideration of fibrinolytic therapy. Currently, standard anticoagulation is considered adequate therapy for patients with intermediate risk PE (PE + Hemodynamically stable). There have been few small studies comparing tPA to on this hemodynamically stable group which did not show any survival benefit. This study aims to detect the effect of tenecteplase therapy on mortality in this intermediate risk group.

Design

  • Multicenter, double-blind, placebo-controlled randomized trial
  • N=1005
  • 76 sites in 13 countries
  • November 2007 – July 2012
  • Inclusion Criteria
    • Age>18
    • Objectively confirmed PE with onset of symptoms <15 days before randomization
    • RV dysfunction confirmed by echo or CT
    • Myocardial Injury confirmed by positive biomarker
  • Exclusion Criteria
    • Hemodynamic Collapse on presentation
    • Known significant bleeding risk
    • Thrombolytic administration within past 4 days
    • IVC filter or thrombectomy within last 4 days
    • Uncontrolled HTN at presentation
    • Treatment with an investigational drug within last 7 days
    • Prior enrollment in this study
    • Hypersensitivity to thrombolytics or anticoagulants used in the study
    • Pregnancy within last 30 days
    • Known coagulation disorder

Interventions

  • Eligible patient’s were randomized using a computerized Internet based system within 2 hours of meeting inclusion criteria
  • Fibrinolytic therapy group received a weight based push dose of tenecteplase over 5 to 10 seconds
  • Placebo group was given a single IV bolus of the same volume and appearance as tenecteplase
  • IV bolus of unfractionated heparin was administered immediately after randomization except for patients who were already administered unfractionated heparin (bolus or infusion), and patients who had received unfractionated heparin or fondaparinux
  • Unfractionated heparin infusions were started in all patients (Start time delayed 12 hours after last LMWH dose and 24 hours after last fondaparinux dose). Infusions were titrated to maintain PTT between 2.0 and 2.5 times the upper limit of normal
  • Patients were followed for 30 days and evaluated for primary, secondary and safety outcomes

Outcomes

  • Primary Outcomes: 2.6% in Tenecteplase group. 5.6% in Placebo group (p=0.02)
  • All-cause mortality within 7 days: 1.2% v 1.8% (p=0.42)
  • Hemodynamic decompensation within 7 days: 1.6% v 5.0% (p=0.002)
  • Safety Outcomes
    • Stroke within 7 days: 2.4% v. 0.2% (p=0.003)
    • Extracranial Major Bleeding within 7 days: 6.3% v. 1.2% (p<0.001)
    • Serious Adverse Events within 30 days: 10.9% v. 11.8% (p=0.63)

Criticisms

Study not powered to find statistically significant difference in mortality

Funding

  • Programme Hospitalier de Recherche Clinique in France
  • Federal Ministry of Education and Research in Germany
  • Boehringer Ingelheim

Source