EM – Critical Care Journal Club

Topic: Use of tenecteplase in patients with intermediate-risk pulmonary embolism

Article: Meyer et al. “Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism.” NEJM 2014.

Resident Reviewer: Emily Zametkin, MBBS

 

Case / Problem

Should we use tenecteplase therapy in patients with intermediate-risk pulmonary embolism (PE)?

How was article selected?

There was interest in trials to guide the use of tenecteplase in patients with confirmed PE in the emergency department.  Blog posts on the topic were reviewed and this article was selected because it was based on a large clinical trial.

Study Description and Research Question

Multi-center, double blind, placebo-controlled randomized trial to answer the question:

Is it clinically effective and safe to administer tenecteplase in addition to heparin in normotensive patients with acute PE and intermediate-risk of an adverse outcome as defined by investigators?

Relevance

There is evidence to support the use of tenecteplase in some patients with hemodynamic compromise in the setting of PE, but little data on its use in patients who are hemodynamically stable but have evidence of cardiac strain.  This article addresses if and when providers should consider using tenecteplase in patients with PE.

 

PICO

Population:

1005 patients with intermediate-risk PE (506 tenecteplase group, 499 placebo group)

Multi-center, multi-national trial in Europe

  • Age > 18 years old
  • PE confirmed by VQ scan, CT angiogram, or pulmonary angiogram with onset of symptoms 15 days or less from randomization
  • Troponin I >0.06 ug/L or troponin T >0.01 ug/L
  • Echocardiogram: RV end-diastolic diameter >30 mm in parasternal long or short axis, right-to-left ventricular end-diastolic diameter >0.9 on apical or subcostal 4-shamber view, hypokinesis of RV free-wall, or tricuspid systolic velocity >2.6 m/sec on apical or subcostal 4-chamber view or right-to-left internal diameter ratio >0.9 on angiogram
  • SBP >90 without significant drop in blood pressure and evidence of end-organ damage

Intervention:

Single weight-based IV dose (over 5-10 seconds) of tenecteplase

  • Dose ranged from 30-50 mg
  • Unfractionated heparin bolus followed by infusion (for goal aPTT of 2-2.5 x upper limit of normal) administered to both treatment and placebo groups except in patients who already received a bolus or who were receiving therapeutic doses of LMWH or fondaparinux (administration delayed 12 and 24 hours, respectively)

Comparison:

Administration of heparin only

Outcomes:

Primary outcomes were death from any cause or hemodynamic decompensation (or collapse) with in 7 days of randomization.  Hemodynamic decompensation was defined as need for CPR, SBP <90 mmHg for >15 minutes, drop in SBP >40 mmHg for >15 minutes with signs of end-organ hypoperfusion, or need for catecholamines to maintain organ perfusion and SBP >90 mmHg, including dopamine at >5 mcg/kg/min.

Secondary outcomes included confirmed symptomatic recurrence of PE within 7 days, death within 30 days, and major adverse events within 30 days.

Safety outcomes included ischemic or hemorrhagic stroke (including conversion of ischemic stroke to hemorrhagic) within 7 days, extracranial major bleeding (moderate to severe) within 7 days, and serious adverse events within 30 days.

 

Appraisal of Internal Validity

Did the experimental and control groups starts out with a similar prognosis?

Exclusion criteria: hemodynamic compromise, coagulopathy or significant bleeding risk excluding anti-platelet therapy, use of thrombolytics in previous 4 days, IVC placement or thrombectomy within 4 days, uncontrolled HTN SBP>180 or DBP>110), treatment with another investigative medications in previous week, prior enrollment in trial, hypersensitivity to trial medications, pregnancy/recent delivery/uncertain pregnancy status, any condition that would place patient at risk with investigational therapy use

  • Exclusion criteria well-defined and replicable
  • Inclusion and exclusion criteria were appropriate given study question
  • Intervention and placebo were well-defined and replicable
  • Group assignment was randomized and concealed
  • Randomization was largely successful- statistically significant difference in LMWH and fondaparinux administration prior to randomization- 33.6% in tenecteplase group vs. 26.6% in placebo group (p=0.02)
  • Patients were analyzed in the groups they were randomized to, 4 did not receive study drug and were not included in safety analysis, 1 informed consent form from a patient in the placebo group was misplaced so this patient was excluded
  • Intention-to-treat analysis
  • Double-blinded
  • Patients were treated equally except for intervention
  • Compliance was measured in terms of who received the drug and who did not- this seems sufficient
  • Outcome measures were well-defined but it is unclear if they are clinically significant
  • Follow-up was complete with no drop-outs
  • Follow-up period was sufficiently long enough but did not discuss clinical significance of treatment
  • Outcome assessment was blinded

 Good internal validity- given study design, bias and confounding minimized as much as possible

 

Primary Results

  • 6 patients (1.2%) in the tenecteplase group and 9 patients in the (1.8%) in the placebo group died in the 7 days following randomization (p=0.42)
    • 4 patients in treatment group died of stroke, 1 of bleeding, and 1 of hemodynamic compromise
    • 3 patients in the placebo group died of hemodynamic compromise, 3 of recurrent PE, 1 of sudden unexplained death, 2 as “other”
  • 8 patients (1.6%) in the tenecteplase group and 25 patients (5%) in the placebo group experienced hemodynamic decompensation or collapse (p=0.002)
  • Overall, primary efficacy outcome occurred in 13 patients (2.6%) in the tenecteplase group as compared with 28 patients (5.6%) in the placebo group (OR 0.44, 95% CU 0.23 to 0.87; p=0.02)

 Of note,

  • Time to primary outcome was similar for both groups (1.54+71 days for treatment, 1.79+1.60 days for placebo)
  • 1 person (0.2%) in tenecteplase group vs. 5 patients (1%) in placebo group had recurrent PE in 7 days (OR 0.2 95% CI 0.02 to 1.69; p=0.12)- 3 of the patients in the placebo group had a fatal PE
  • Safety outcomes (intervention vs. placebo)
    • Major extracranial bleeding (moderate or severe) in 32 (6.3%) for treatment group vs. 6 (1.2%) (OR 5.55 95% CI 2.3 to 13.39; p<0.001)
    • Major bleeding as defined by ISTH occurred in 58 (11.5%) vs. 12 (2.4%) of patients
    • Stroke in 7 days occurred in 12 (2.4%) in treatment group vs. 1 (0.2%) (OR 12.10 95% CI 1.57 to 93.30; p=0.003)- 10 strokes in the treatment group were hemorrhagic and the stroke in the control group was also hemorrhagic
    • Serious adverse events in 30 days occurred in 55 (10.0%) in the treatment group and 59 (11.8%) (OR 0.91 95% CI 0.62-1.34; p=0.63)
  • 8 patients in tenecteplase group vs. 15 in the placebo group required mechanical ventilation
  • 1 patient in tenecteplase group vs. 2 in the placebo group required surgical embolectomy
  • Death from any cause within 30 days of randomization was 12 (2.4%) in tenecteplase group vs. 16 (3.2%) in placebo group (OR 0.73 95% CI 0.34-1.57; p=0.42)
  • Patients in the tenecteplase group were more likely to be re-hospitalized within 30 days or still be in the hospital at 30 days

 

External Validity

These findings are generalizable.  However, no mention of race of the patients and presence of comorbidities such as prior, stroke, diabetes, ect.  This population is European while we are practicing in the US in a city hospital that serves a socioeconomically and racially diverse population.

Utility to Practice

I will use tenecteplase to treat intermediate-risk PE, but will be unlikely to use it in patients who are > 75 years old based on this study.  Follow-up studies on the clinical significance of the treatment should also be reviewed.

Criticisms:

  • Not powered for differences in mortality
  • Long-term outcomes- rates of heart failure, death, pulmonary hypertension not reported on
  • Unclear if treatment impacts quality of life

 

Resident Reviewer: Emily Zametkin, MBBS
Faculty Editor: Alex Sheng, MD