1. Fibrinolysis in intermediate risk PE
Journal Club 7th July
Irene Doo

2. Acute PE Incidence Mortality
0.3 per 1000 people per year in Australia (7000)
~4.5% massive PE
Mortality
15% at 90 days with RV failure most common COD
Systematic reviews have shown that RV dysfunction increases mortality in pts with haemodynamically stable PE

3. Acute PE
Fibrinolysis in massive PE – accepted despite minimal evidence
IIa recommendation in AHA guidelines
Fibrinolysis in submassive PE controversial!
Lack of trials (less than 1000 pts total RCTs in last 40 yrs)
Lack of evidence of improved mortality
MOPPETT trial suggested significant reduction in pulmonary hypertension at 2 years.

4. Background Submassive = PE with RV strain or PHT w/o shock
256 pts: 118 alteplase + hep, 138 hep alone
Deaths: 4 in treatment, 3 in placebo
Escalation of tx: 12 in treatment, 38 in placebo
Summary: No difference in mortality; sig. more open label lysis in placebo group; no difference in bleeding; No haemorrhagic stroke in either group

5. PEITHO

6. Rationale
Konstantinides_PEITHO_ACC 2013

7. Objectives

8. PEITHO
Randomised, double blinded, placebo controlled trial of 1005 pt with “intermediate risk” PE)
Looking at clinical efficacy and safety
76 sites in 13 countries in Europe
Tenectoplase + heparin vs placebo + heparin
Sample size needed 474 pts in each group for 80% power to detect difference between a placebo group proportion of 0.07 and tenecteplase group proportion of 0.03

9. Tenecteplase dose

11. Inclusion Criteria Age >18
PE diagnosed on CTPA, V/Q or PA with onset of symptoms 15 days or less before randomisation
RV dysfunction on TTE or CT
Myocardial dysfunction with elevated troponin
(TropI> 0.06microg/L, or TropT >0.01microg/L)

12. RV dysfunction At least one of the following on ECHO Or CT evidence of
RV EDD >30mm (PLA, or PSA views)
RV: LV EDD >0.9 (apical or subcostal 4 chamber)
Hypokinesis of RV free wall (any view)
Tricuspid systolic velocity >2.6m/s (apical or subcostal 4 Chamber)
Or CT evidence of
RV:LV internal diameter ratio (as measured in transverse plane) >0.9

13. Diagnosis of submassive PE

14. Exclusion Criteria Haemodynamic decompensation at presentation
Known significant bleeding risk
Previous lysis in last 4 days
IVC filter insertion or pulmonary thrombectomy in last 4 days
Uncontrolled HTN SBP>180 or DBP>110 at randomization
Previous enrolment in this trial
Hypersensitivity to trial drugs
Pregnancy, lactation, or parturition in last 30days
Any other condition that investigator felt would place pt at increased risk if lysed

15. Primary outcome

16. Secondary efficacy and safety outcomes

20. Results

21. Outcomes

22. Complications

23. Results

25. Limitations Troponin thresholds very low
Were patients sick enough? – mortality rate in placebo group 1.8% at 7d, 3.2% at 30d
CT evidence of RV dysfunction ? Validation
Did the bolus of heparin and infusion given prior to lysis contribute to bleeding risk?
Should the thrombolysis dose be reduced?
No details of longer term follow up in results

26. Summary No difference in mortality rate between groups
Lysis did decrease rate of haemodynamic collapse (3 fold)
Lysis 10 fold increase in ICH (NNH 50) and 5 fold increase in major bleeding (NNH 16)
More trials needed to determine subgroup of pts with submassive PE in whom risk of mortality outweighs risk of bleeding

27. Questions

28. Appendices

29. Cause of death

30. APTT in both groups

31. Primary efficacy outcome in non prespecified subgroups