Pulmonary Embolism Thrombolysis Study - PEITHO

Description:

The goal of the trial was to evaluate fibrinolysis compared with placebo among normotensive patients with acute intermediate-risk pulmonary embolism.

Hypothesis:

Fibrinolysis will improve outcomes.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel

Patient Populations:

  • Normotensive patients ≥18 years with acute (onset of symptoms <15 days before randomization) intermediate-risk pulmonary embolism and evidence of right ventricular dysfunction (confirmed by echocardiography or spiral CT) and myocardial injury (elevated troponin I or T)

    Number of enrollees: 1,006
    Duration of follow-up: 30 days
    Mean patient age: 67 years
    Percentage female: 52%

Exclusions:

  • High-risk pulmonary embolism
  • Known bleeding risk
  • Fibrinolysis within the last 4 days
  • Vena cava filter or pulmonary thrombectomy within the last 4 days
  • Known coagulation disorder
  • Treatment with an investigational drug

Primary Endpoints:

  • All-cause mortality or hemodynamic collapse
  • Hemodynamic collapse defined as:
    - Need for cardiopulmonary resuscitation,
    - Systolic blood pressure <90 mm Hg with end-organ hypoperfusion, or
    - Need for pressor support

Secondary Endpoints:

  • All-cause mortality
  • Hemodynamic collapse
  • Pulmonary embolism recurrence
  • Nonintracranial major bleeds
  • Total strokes
  • Serious adverse events

Drug/Procedures Used:

Normotensive patients with acute intermediate-risk pulmonary embolism were randomized to fibrinolysis with tenecteplase (30-50 mg depending on body weight; n = 506) versus placebo (n = 500).

Both study groups received unfractionated heparin on day 1, which was later converted to warfarin.

Principal Findings:

Overall, 1,006 patients were randomized. The mean age was 67 years, 52% were women, 25% had previous venous thromboembolism, and mean systolic blood pressure was 131 mm Hg. Confirmation of right ventricular dysfunction was made by echocardiography in 55%, echocardiography and spiral computed tomography (CT) in 30%, and spiral CT in 15%.

The primary outcome of all-cause mortality or hemodynamic collapse at 7 days occurred in 2.6% of the fibrinolysis group vs. 5.6% of the placebo group (p = 0.02). Benefit was observed among patients ≤75 years (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.12-0.85); however, wide CIs included possible harm among patients ≥75 years (HR 0.63, 95% CI 0.23-1.66; p for interaction = 0.36).

Outcomes at 7 days:
- All-cause mortality: 1.2% vs. 1.8% (p = 0.42), respectively
- Hemodynamic collapse: 1.6% vs. 5.0% (p = 0.002), respectively
- Extracranial major bleeds: 6.3% vs. 1.2% (p < 0.001), respectively; harm was observed among patients ≤75 years (HR 2.80, 95% CI 1.00-7.86), and especially among patients >75 years (HR 20.38, 95% CI 2.69-154.53; p for interaction = 0.09)
- Total strokes: 2.4% vs. 0.2% (p = 0.003), respectively; this was driven by an increase in hemorrhagic strokes: 10 vs. 1, respectively
- Serious adverse events: 5.7% vs. 7.8%, respectively

- All-cause mortality 30 days: 2.4% vs. 3.2% (p = 0.42), respectively

Interpretation:

Among normotensive patients with intermediate-risk pulmonary embolism, the use of fibrinolysis was feasible. Fibrinolysis was associated with a reduction in death or hemodynamic collapse at 7 days; however, there was a significant excess in both extracranial and intracranial hemorrhage. The excess in extracranial hemorrhage appeared to mostly occur among patients >75 years of age. A reduction in the dose of tenecteplase has been shown to reduce intracranial hemorrhage among the elderly with ST-segment elevation myocardial infarction. Such a strategy would need to be tested in the pulmonary embolism population. At the present time, the use of fibrinolytic therapy for pulmonary embolism remains confined to hemodynamically unstable high-risk patients.

References:

Meyer G, Vicaut E, Danays T, et al., on behalf of the PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.

Presented by Dr. Stavros Konstantinides at ACC.13, San Francisco, March 11, 2013.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Lipid Metabolism, Interventions and Imaging, Interventions and Vascular Medicine, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging

Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Follow-Up Studies, Pulmonary Embolism, Warfarin, Body Weight, Heparin, Venous Thromboembolism, Blood Pressure, Fibrinolytic Agents, Tomography, Spiral Computed, Ventricular Dysfunction, Right, Intracranial Hemorrhages, Troponin I, Fibrinolysis, Confidence Intervals, Tissue Plasminogen Activator, Echocardiography


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