Should you use fibrinolysis for patients with intermediate-risk PE?

Author: Maha Salama, PGY-3

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Background:

• ~ 10% of all patients with acute PE die within 3 months of diagnosis.
• Patients with acute RV dysfunction and evidence of myocardial injury without hemodynamic compromise may be at intermediate risk for adverse early outcome.
• The use of fibrinolytics in patients with massive PE has demonstrated clear clinical benefit.
• TNKase is a tPA

Article Reviewed: 

• “Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism” Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. New England Journal of Medicine. 2014;370:1402-11

Clinical Question:

• The Pulmonary Embolism Thrombolysis (PEITHO) trial was designed to investigate the clinical efficacy and safety of fibrinolytic therapy with a single-bolus injection of tenecteplase, in addition to standard anticoagulation therapy with heparin in normotensive patients with acute PE and intermediate risk of an adverse outcome.

Population:

• Adult normotensive patients with symptomatic acute PE with evidence of RV
  dysfunction and myocardial injury

Outcomes:

• Primary:
  • Death or hemodynamic decompensation (or collapse) within 7 days after
    randomization
  • Hemodynamic collapse or decompensation defined as a persistent, isolated drop in systolic blood pressure
• Secondary:
  • Major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization
  • Confirmed symptomatic recurrence of PE within 7 days
  • Death within 30 days
  • Major adverse events within 30 days
• Intervention:
  • Tenecteplase plus heparin in normotensive patients with intermediate risk PE
  • Single weight based IV bolus (over 5 – 10 sec) of tenecteplase (dose range 30mg-50mg)
  • IV bolus of heparin immediately after randomization in both group
    • Heparin infusion rate adjusted to achieve and maintain PTT 2-2.5x upper limit of normal
• Control:
  • Placebo plus heparin in normotensive patients with intermediate risk PE
  • Single IV bolus of same volume and appearance as bolus of tenecteplase
• Design:
  • Multicenter, randomized double-blind, placebo-controlled trial
  • Randomization with computerized internet based system; stratified by center and within centers performed in blocks
  • Occurred within 2 hrs of finding RV dysfunction and myocardial injury
  • Total of 1006 patients at 76 sites in 13 countries between Nov 2007-Jul 2012
• Inclusion Criteria:
  • Age ≥ 18
  • Objectively confirmed acute PE with onset of sx ≤ 15 days before randomization
  • Right ventricular dysfunction on echocardiography or CT
  • Myocardial injury as indicated by positive cardiac troponin or troponin T

Primary Results:

• 1006 patients underwent randomization
  • 1005 included in intention-to-treat analysis
• N = 506 tenecteplase + heparin
  • 13 patients (2.6%) with death or hemodynamic decompensation
  • 6 patients died between randomization and day 7
  • 8 patients (1.6%) with hemodynamic decompensation or collapse
• N = 500 placebo + heparin (total 499; loss of one informed consent form)
  • 28 patients (5.6%) with death or hemodynamic decompensation
  • 9 patients died between randomization and day 7
  • 25 patients (5%) with hemodynamic decompensation or collapse

Secondary Results:

• N = 506 tenecteplase + heparin
  • 12 patients (2.4%) died by day 30 of randomization
  • 32 patients (6.3%) had extracranial bleeding
  • 12 patients (2.4%) experienced a stroke
    • 10 of which were hemorrhagic
      • 6 were alive 30 days after randomization-case fatality of 40%; mild
        or mod disability persisted in most of the survivors
  • Major bleeding occurred between randomization and day 7 in 58 patients (11.5%)
• N = 499 placebo + heparin
  • 16 patients (3.2%) died by day 30 of randomization
  • 6 patients (1.2%) had extracranial bleeding
  • 1 patient had a stroke-hemorrhagic
  • Major bleeding occurred in 12 patients (2.4%)
• By day 30, 12 patients in the intervention group and 16 patients in the control group died
• 

Critical Findings:

• Patients with intermediate risk PE who were treated with standard AC had 5.6% incidence of death or hemodynamic decompensation within the first 7 days after randomization
• A single bolus injection of tenecteplase resulted in significantly lower risk of primary outcome (2.6%)
• Fibrinolytic tx associated with 2% risk of hemorrhagic stroke and 6.3% risk of major extracranial hemorrhage

Strengths:

• Study design
• Standardized treatment

Limitations:

• Study not powered to detect differences in rates of death
• Nonspecific parameters for hemodynamic compromise

Discussion:

• Use of fibrinolytic therapy in intermediate risk PE was associated with reduced risk of hemodynamic decompensation or death in normotensive patients
• Suggestive finding that fibrinolysis is associated with lower risk of bleeding in younger patients than in patients over 75 yrs of age; not clinically significant
• Authors’ Conclusions:
  • “Our results indicate that prompt fibrinolysis can reduce the risk of hemodynamic decompensation or death in normotensive patients who have acute pulmonary embolism with right ventricular dysfunction, as indicated by echocardiography or CT, and myocardial injury, as indicated by a positive cardiac troponin test.”
• Our Conclusions:
  • There is a demonstrated benefit to the use of fibrinolytics in the treatment of intermediate risk PE though at increased risk of adverse bleeding events.
• Potential to Impact Current Practice:
  • Potential to treat intermediate risk PE which significant clinical implications in regards to patient morbidity/mortality; weighed against increased risk of bleeding events particularly hemorrhagic stroke.
  • Potential of half dose tenecteplase? Benefit demonstrated in STEMI
• Clinical Bottom Line:
  • Weigh the benefits of treatment of acute intermediate risk PE against the increased risk of bleeding and other side effects of tPA.