KT Evidence Bite: Fibrinolysis in Intermediate PE

Editor’s note: This is a series based on work done by three physicians (Patrick Archambault, Tim Chaplin, and our BoringEM Managing editor Teresa Chan) for the Canadian National Review Course (NRC). You can read a description of this course here.

The NRC brings EM residents from across the Canada together in their final year for a crash course on everything emergency medicine. Since we are a specialty with heavy allegiance to the tenets of Evidence-Based Medicine, we thought we would serially release the biggest, baddest papers in EM to help the PGY5s in their studying via a spaced-repetition technique. And, since we’re giving this to them, we figured we might as well share those appraisals with the #FOAMed community! We have kept much of the material as drop downs so that you can quiz yourself on the studies.

Paper: Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism

Citation:

Meyer, G., Vicaut, E., Danays, T., Agnelli, G., Becattini, C., Beyer-Westendorf, J., … & Konstantinides, S. V. (2014). Fibrinolysis for patients with intermediate-risk pulmonary embolism. New England Journal of Medicine, 370(15), 1402-1411. PMID: 24716681

Nickname of study:

PLEITHO Trial

Summarized by: Patrick Archambault
Reviewed by: Teresa Chan & Tim Chaplin

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Clinical Question

In patients with intermediate-risk PE (signs of RV dysfunction and cardiac injury) does fibrinolysis improve clinical outcomes?

Population	Normotensive adult patients with intermediate-risk pulmonary embolism: (1) right ventricular dysfunction on echocardiography (see footnote) or computed tomography AND (2) positive troponin I or T
Intervention	tenecteplase (full bolus dose over 5-10 seconds based on weight: >60kg=30 mg; >90kg=50mg) plus heparin started immediately after randomization
Control	placebo plus heparin
Outcome	Primary: death or hemodynamic decompensation (or collapse) within 7 days Secondary: 1) death < 7 days after randomization, (2) hemodynamic decompensation < 7 days, (3) confirmed symptomatic recurrence of PE < 7 days, (4) death < 30 days, (5) major adverse events < 30 days

Methods

This was a randomized, double-blind trial, with intention-to-treat analysis

Results

Primary outcome (benefit)

Death OR hemodynamic decompensation was 2.6% (TNK) vs 5.6% (placebo)
OR=0.44 (95% CI 0.23-0.87, p=0.02)
This results in an NNT of 33

Secondary outcome (harms)

Extracranial bleed: 6.3% (TNK) vs 1.2% (placebo) p<0.001
Stroke: 2.4% (TNK) vs 0.2% (placebo) p<0.003
This results in a NNH of 45

Conclusions

Normotensive patients with intermediate-risk pulmonary embolism benefit from treatment with a single intravenous bolus of tenecteplase, but at a higher risk of ICH.

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Take Home Point

Normotensive patients with intermediate-risk pulmonary embolism benefit from treatment with a single intravenous bolus of tenecteplase (but effect driven by decrease in hemodynamic collapse not the death outcome) and with a higher risk of ICH. More studies are ongoing about the use of reduced doses of TNK. In June 2014, a meta-analysis was published in JAMA.

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EBM Considerations

Co-intervention: Were the hemorragic complications due to previous LMWH or fondaparinux given before randomization?
Compound outcomes: the efficacy of thrombolysis was mainly driven by the prevention of hemodynamic decompensation more than its effect on mortality. Hemodynamic collapse was defined as:
- need for CPR or
- systolic BP <90mmHg for >15 minutes or
- drop of systolic BP by at least 40mmHg for at least 15 min with signs of endorgan hypoperfusion (cold extremities or low urinary output < 30 mL/h or mental confusion or
- need for catecholamine administration to maintain adequate organ perfusion and a systolic blood pressure of > 90 mm Hg (including dopamine at the rate of > 5 micrograms/ kg per minute)
Chosen Dose: To reduce risk of ICH in patients over 75 years, should we adopt a policy to reduce dose by 50%? (NB. In a recently published prehospital trial of TNK in STEMI, there were no cases of intracranial hemorrhage when the dose was reduced by 50% in patients 75 years of age or older. (PMID: 23473396 Full text click here). A reduced dose strategy also has merit: see MOPETT trial.