Pulmonary Embolism Thrombolysis Study - PEITHO

Apr 19, 2014
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Programme Hospitalier de Recherche Clinique in France, Federal Ministry of Education and Research in Germany, and Boehringer Ingelheim
Date Presented:
01/01/2013
Date Published:
01/01/2014
Date Updated:
04/19/2014
Original Posted Date:
04/19/2014
References

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.

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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