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.
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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