1. Thrombolysis therapy for Pulmonary Embolism
Journal Club
Dr Sarah Lambert
July 2017

2. Evidence base

3. WUTH Policy for thrombolysis
Massive PE causing haemodynamic instability
Systolic <90mmHg
Pressure drop of ≥40mmHg for more than 15 minutes
Hypotension is NOT caused by
Cardiac arrhythmia
Hypovolaemia
Sepsis
CTPA
ECHO
Acute right ventricular dysfunction (with no other explanation)
Free floating thrombus in the right atrium or right ventricle

4. Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial Jerjes-Sánchez et al. Journal of Thrombosis and Thrombolysis (January 1995)
Single centre RCT
Streptokinase and IV heparin verses IV heparin alone
Outcomes/measurements not stated in the paper
Inclusion criteria
>15 years old
Previously fit and well
PE diagnosis by high clinical suspicion or V/Q scan
>9 segments obstructed on V/Q scan +/- cardiogenic shock
<9 segments obstructed but right heart strain

5. Streptokinase + heparin [n=4]
Results
Streptokinase + heparin [n=4]
Heparin alone [n=4]
Age
51 +/- 22.8
49 +/
Onset PE (hr)
2.5
34.75
Time to improvement (hr) 1
n/a
Death
4 (100%) [p=0.02]
RV akinesia 4
PASP 97 32
93.75
91.25
No adverse bleeding observed
Study terminated due to 100% death rate in control group
Follow up at 2 years – all patients that received thrombolysis were
Functional class 1
Normal PA pressure
No recurrence of PE

6. Discussion points
Randomisation? – all those assigned to control group had delayed presentation
Researcher bias
Patient bias
Sample size small
Diagnosis of PE confirmed by V/Q scan retrospectively
Initial diagnosis made on clinical basis
Variability in onset of symptoms to presentation
Included patients they said they would exclude – patients that had delayed presentations was because of multiple PE episodes
Outcomes/measures not stated in design
Unknown who received mechanical ventilation/support
Study terminated - deemed unethical to continue

7. Fibrinolysis for Patients with Intermediate Risk Pulmonary Embolism Meyer et al. The New England Journal of Medicine (2014)
Randomised, double-blind trial (multicentre 76 sites, 13 countries)
Tenectoplase plus heparin v’s placebo plus heparin
Patient criteria
Normotensive
Right ventricular dysfunction on ECHO or CT
Myocardial injury (raised troponin)
Primary Outcome
Death or haemodynamic decompensation within 7 days
Safety outcomes
Stroke, extracranial bleed, serious adverse events (30 days)

8. Methodology Study size – 1005 patients
Randomisation within 2 hours of investigator being made aware of patient
Fibrinolysis was given as single IV bolus
Unfractionated heparin started immediately after randomisation with a bolus then infusion
Analysis done by independent person

9. Results Efficacy Outcomes Tenectoplase + heparin [N=506]
Placebo + heparin
[n=499]
Primary outcome (death/ haemodynamic collapse)
13 (2.6%)
28 (5.6) [P=0.02]
Mechanical Ventilation 8 15
Hypotension (requiring support)
8 (3)
18 (14)
CPR 1 5
Safety Outcomes
Tenectoplase + heparin
Placebo + heparin
Major bleed
58 (11.5%)
12 (2.4%)
Extracranial bleeding
32 (6.3%)
6 (1.2%) [P<0.001]
Stroke
1 (0.2%) [P=0.003]
Haemorrhagic Stroke
10 (2.0%)
1(0.2%)
Death at 7 days
6 (1.2%)
9 (1.8%) [P=0.42]
Death at 30 days
16 (3.2%) [P=0.42]

10. Conclusions
Fibrinolysis in intermediate risk PE had a lower incidence of death within the first 7 days
Fibrinolytic treatment associated with a 2% risk of haemorrhagic stroke and 6.3% risk of extracranial haemorrhage
Mortality rate in control group may be under represented
Higher risk of bleeding in patients >75 years (not significant)
Weigh up the benefits verses increased side effects in this patient group

11. Discussion Large double blind study (gold standard)
Results are in keeping with other studies
Death rate could have been higher in the control group had they not been closely monitored and prompt correction of adverse features i.e. drop in blood pressure
Some variability in treatment – In 303 patients (30.1%) heparin bolus was omitted due to already having received treatment fondiparinux or LMWH

12. Final thoughts
Few trials evaluating the effectiveness of systemic thrombolysis in massive PE
Widely accepted that thrombolysis is likely to reduce mortality in massive PE
Multi-disciplinary decision despite protocol
Benefit verses risk
Not clear cut especially in ‘sub-massive’ PE or haemodynamically stable patient
Reduced dose in elderly to reduce risk of bleeding?
Bolus verses infusion
Peripheral verses central
Agent

13. Thank you Any questions

14. Diagnosis CTPA ECHO Massive PE causing haemodynamic instability
Systolic <90mmHg
Pressure drop of ≥40mmHg for more than 15 minutes
Hypotension is NOT caused by
Cardiac arrhythmia
Hypovolaemia
Sepsis
CTPA
ECHO
Acute right ventricular dysfunction (with no other explanation)
Free floating thrombus in the right atrium or right ventricle

15. Absolute Contraindications
Taking oral anticoagulants (discuss with haematologist)
Significant bleeding disorder at present or within 6 months
Manifest or recent severe or dangerous bleeding
Recent major trauma
Surgery or head injury within 3 weeks
Recent stroke (within 6 months) or history of haemorrhagic stroke
GI bleed within a month
Severe liver disease
Haemorrhagic diasthesis
Aortic dissection
Any history of CNS damage
Recent puncture of a non compressible blood vessel
Bacterial endocarditis
Pericarditis
Acute pancreatitis

16. Relative contraindications
Systolic >180mmHg
Diastolic >100mmHg
Prolonged chest compression
Active peptic ulcer
Other significant risk of haemorrhage
Pregnant or 1 week post partum
Other cautions – Risk of anaphylaxis is increased in patients taking ACE inhibitors