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2. Pulmonary Embolism Who Should Receive Thrombolysis?
Stavros V. Konstantinides, MD, FESC
Professor, Clinical Trials in Antithrombotic Therapy
Center for Thrombosis und Hemostasis, University of Mainz, Germany
Professor of Cardiology
Democritus University of Thrace, Greece 2

3. Disclosures
Lecture fees (moderate): Bayer HealthCare, Boehringer Ingleheim, Daiichi Sankyo, Pfizer – Bristol-Myers Squibb
Consultancy fees (moderate): Bayer HealthCare, Boehringer Ingleheim, Daiichi Sankyo, Pfizer – Bristol-Myers Squibb
Institutional research support: Bayer HealthCare

4. Risk-adjusted management of acute PE
What is intermediate-risk (submassive) PE?
Do we need “revascularization/reperfusion” for intermediate-risk PE?
Is thrombolysis safe for everybody? What alternative/additional options do we have?
What are the implications of the recent trials? 4

5. Resolution of RV dysfunction with alteplase
Echocardiography (paradoxical septal wall)
rtPA + Heparin
Heparin alone
S Konstantinides, Am J Cardiol 1998;82:

6. pes Resolution of RV dysfunction with tenecteplase
Time course of R/L end-diastolic dimension ratio
p =0.04
p = ns
p= 0.043
pes
C Becattini et al. Thromb Res 2010

7. Elevated early risk beyond massive PE?
Parameter
Tests / Findings
RV Dysfunction
RV dilatation, hypokinesis or pressure overload on echocardiography
RV dilatation on spiral CT
[BNP or NT-proBNP elevation]
[ right heart pressures at RHC]
Myocardial injury
Cardiac troponin T or I positive
[H-FABP]
[Myoglobin]

8. Thrombolysis for submassive PE (2002)
30%
P=0.001
Alteplase (n=118)
32 (23.2%)
Placebo (n=138)
20%
Incidence
P=0.7
P=0.2
P=0.33
P=0.85
9 (7.6%)
10%
8 (5.8%) 4
(3.4%) 3
(2.2%)
3 (2.5%)
3 (2.5%)
3 (2.2%)
1 (0.7%)
Death
CPR
Shock
Intubation
Emergency
Thrombolysis
S Konstantinides. N Engl J Med 2002;347:1143

9. RV dysfunction on CT: LOW positive predictive value
Meta analysis (27 studies, 4767 patients)
Cut-off for RV:LV >1.0 (6 studies; 1678 pts)
OR for 30-d death, 2.81 ( )
Hemodynamically stable pts (6 studies; n=2254)
OR for 30-d death, 1.64 ( )
OR for 3-month death, 5.14 ( )
30-d PE-related death (7 studies)
OR, 7.7 ( )
NPV, 99%; PPV, 5%
C Becattini. Eur Respir J 2014; Epub ahead of print

10. Biomarkers (cTn) in PE: LOW positive predictive value
Author
Pts (n)
Marker
Ref.
value*
Positive (%)
NPV (%)
PPV (%)
Giannitsis, 2000 56
Trop T
0.10 32 97 44
Konstantinides, 2002
106
Trop I
0.07 41 98 14
0.04 37 12
Janata, 2003
0.09 11 99 34
Pruszczyk, 2003 64
0.01 50
100 25
* in ng/mL
N Kucher and S Z Goldhaber. Circulation 2003;108:2191

11. +? Going further: Biomarkers combined with imaging RV Dysfunction
Parameter
Tests / Findings
RV Dysfunction
RV dilatation, hypokinesis or pressure overload on echocardiography
RV dilatation on spiral CT
[BNP or NT-proBNP elevation]
[ right heart pressures at RHC]
Myocardial injury
Cardiac troponin T or I positive
[H-FABP]
[Myoglobin] +?

12. Complication risk (OR, 95% CI)
Biomarkers combined with imaging (2005)
Patient group
Complication risk (OR, 95% CI)
Troponin T-negative (<0.04 ng/ml)
Troponin-positive, echo-negative
3.70 ( )
P=0.107
Troponin-negative, echo-positive
5.56 ( )
P=0.055
Both troponin- and echo-positive
10.00 ( )
P=0.004
~ 15% of all PE patients
L Binder, S Konstantinides. Circulation 2005;112:

13. Risk-adjusted management of acute PE
What is intermediate-risk PE?
Do we need “revascularization” for intermediate-risk PE?
Is thrombolysis safe for everybody? What alternative/additional options do we have?
What are the implications of the trials? 13

14. PEITHO: Design Primary Outcome, Secondary Outcomes
Confirmed acute symptomatic PE
Primary Outcome, Secondary Outcomes
TNK
Absence of hemodynamic collapse
Seconray Outomes, SAE
UFH, LMWH or Fondaparinux
UFH infusion
Long-term Follow-up
<2 h
DOUBLE BLIND
Confirmed RV dysfunction + myocardial injury
VKA R
Placebo
UFH, LMWH or Fondaparinux
UFH infusion
UFH bolus i.v.
VKA
Day 2
Day 7
Day 30
Day 180
S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1 14

15. PEITHO: Analyzed population
Rivaroxaban clinical development
PEITHO: Analyzed population
Tenecteplase
Placebo
Randomized (N=1006)
506
500
1 ICF unavail.
ITT Population
506
499
Safety population*
506
499
EINSTEIN PE: patient flow
This slide shows the patient flow in the EINSTEIN PE study.
*all ITT patients received study medication
First Patient In: November 2007; Last Patient Out: August 2012
The PEITHO Investigators. N Engl J Med 2014;370(15): 15

16. Thrombolysis superior
PEITHO: Primary efficacy outcome
Tenecteplase (n=506)
Placebo (n=499)
P value n
(%)
All-cause mortality or hemodynamic collapse within 7 days of randomization 13
(2.6) 28
(5.6)
0.015
0.23
0.44
0.88
Verified against source data tables sent for the NEJM publication
1.00
2.00
Odds ratio
Thrombolysis superior
ITT population
The PEITHO Investigators. N Engl J Med 2014;370(15): 16 16 16

17. PEITHO: Secondary efficacy outcomes
Tenecteplase (n=506)
Placebo (n=499)
P value n
(%)
All-cause mortality within 7 days 6
(1.2) 9
(1.8)
0.43
Hemodynamic collapse
within 7 days 8
(1.6) 25
(5.0)
0.002
Need for CPR 1 5
Hypotension / blood pressure drop 18
Catecholamines 3 14
Resulted in death
Verified against source data tables sent for the NEJM publication
ITT population
The PEITHO Investigators. N Engl J Med 2014;370(15): 17 17 17

18. PE risk assessment: What did we learn?
‘Intermediate-risk patient’, not just ‘intermediate-risk PE’
Acute pressure overload
(RV dysfunction)
Preexisting cardiovascular disease
Other serious comorbidity
(cancer)
Recurrent PE
(residual DVT)
Presence of a PFO
Presence of a PFO
Presence of a PFO
Poor prognosis

19. Original and simplified pulmonary embolism severity index (PESI)

20. Original and simplified pulmonary embolism severity index (PESI)

21. Classification of early mortality risk
aPESI Classes III to V indicate moderate to very high 30-day mortality risk; sPESI >1 point(s) indicate high 30-day mortality risk.
bEchocardiographic criteria of RV dysfunction include RV dilatation and/or an increased end-diastolic RV/LV diameter ratio (in most studies, the reported threshold value was 0.9 or 1.0); hypokinesia of the free RV wall; decreased tricuspid annulus plane systolic excursion (TAPSE); or combinations of the above. On computed tomographic (CT) angiography (four-chamber views of the heart), RV dysfunction is defined as an increased end-diastolic RV–LV diameter ratio (with a threshold of 0.9 or 1.0).
cMarkers of myocardial injury (e.g. elevated cardiac troponin I or T concentrations in plasma), or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic peptide concentrations in plasma).
dNeither calculation of the PESI (or sPESI) nor laboratory testing is considered necessary in patients with hypotension or shock.
ePatients in the PESI class I-II, or with sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests, are also to be classified into the intermediate-low risk category. This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

22. Risk-adjusted management of acute PE
What is intermediate-risk PE?
Do we need “revascularization” for intermediate-risk PE?
Is thrombolysis safe for everybody? What alternative/additional options do we have?
What are the implications of the trials? 22

23. PEITHO: Safety outcomes (within 7 days of randomization)
Tenecteplase (n=506)
Placebo (n=499)
P value n
(%)
Non-intracranial bleeding
Major 32
(6.3) 6
(1.5)
<0.001
Minor
165
(32.6) 43
(8.6)
Strokes by day 7 12
(2.4) 1
(0.2)
0.003
Hemorrhagic 10
Ischemic 2
Verified against source data tables sent for the NEJM publication
ITT population
The PEITHO Investigators. N Engl J Med 2014;370(15): 23 23 23

24. PEITHO 6-month follow-up: all-cause mortality
Tenecteplase (n=486)
Placebo (n=474)
P value N
(%) n
All-cause mortality within 180 days 35
(7.0) 30
(6.1)
0.57
The PEITHO Investigators; ESC 2014 24 24 24

25. PEITHO 6-month follow-up: day 31 – day 180
Tenecteplase (n=486)
Placebo (n=474)
P value n
(%)
All-cause mortality
between day 30 and 180 23
(4.7) 14
(3.0)
0.15
Cancer 9 4
Stroke 1
Bleeding 2
Respiratory failure / pneumonia
Sudden unexplained death
Unknown
Other 3 5
The PEITHO Investigators; ESC 2014 25 25 25

26. PEITHO: Efficacy versus safety according to age (?)
≤75 years >75 years
Death or
hemodynamic collapse (primary EP) %
Stroke without primary EP (not leading to death or hemodynamic collapse)
Verified against source data tables sent for the NEJM publication
placebo
TNK
placebo
TNK N
ITT population
The PEITHO Investigators. N Engl J Med 2014;370(15): 26 26 26 26

27. Reduced-dose thrombolysis ?
121 patients with „moderate“ PE
Thrombus in >2 lobar arteries plus >2 symptoms/signs of PE
No RV dysfunction required
Patients received <50% of rtPA dose
Pulmonary hypertension or PR recurrence in 16% of thrombolyzed pts vs. 63% of controls (P<0.001).
No major or minor bleeds!
M. Sharifi. Am J Cardiol 2013;111:

28. Reduced-dose thrombolysis ?
After the dose reduction [by 50%] of tenecteplase in patients 75 years of age or older, there were no cases of intracranial hemorrhage (0 of 97) as opposed to 8.1% (3 of 37) before protocol amendment….
PW Armstrong. N Engl J Med 2013 ;368:

29. Ultrasound-assisted, catheter-directed thrombolysis
Ultrasound- accelerated, reversible disaggregation of uncrosslinked fibrin, (microsonic core wire containing ultrasound elements);
Infusion of recombinant tissue plasminogen activator (5.2 F, multi-sidehole infusion catheter)
6F sheath for unilateral, 10 F for bilateral insertion
Engelberger RP and Kucher N. Eur Heart J 2014;35:

30. Ultrasound-assisted, catheter-directed thrombolysis
Engelberger RP and Kucher N. Eur Heart J 2014;35:

32. Courtesy Drs Piazza and Goldhaber

36. Risk-adjusted management of acute PE
What is intermediate-risk PE?
Do we need “revascularization” for intermediate-risk PE?
Is thrombolysis safe for everybody? What alternative/additional options do we have?
What are the implications of the recent trials? 36

37. Risk-adjusted management algorithm
aIf echocardiography has already been performed during diagnostic work-up for PE and detected RV dysfunction, or if the CT already performed for diagnostic work–up has shown RV enlargement (RV/LV (left ventricular) ratio ≥0.9, a cardiac troponin test should be performed except for cases in which primary reperfusion is not a therapeutic option (e.g. due to severe comorbidity or limited life expectancy of the patient).
bMarkers of myocardial injury (e.g. elevated cardiac troponin I or T concentrations in plasma), or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic peptide concentrations in plasma). If a laboratory test for a cardiac biomarker has already been performed during initial diagnostic work-up (e.g. in the chest pain unit) and was positive, then an echocardiogram should be considered to assess RV function, or RV size should be (re)assessed on CT.
cPatients in the PESI Class I-II, or with sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests, are also to be classified into the intermediate-low risk category. This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index. These patients are probably no candidates for home treatment.
dThrombolysis, if (and as soon as) clinical signs of haemodynamic decompensation appear; surgical pulmonary embolectomy or percutaneous catheter-directed treatment may be considered as alternative options to systemic thrombolysis, particularly if the bleeding risk is high.
eMonitoring should be considered for patients with confirmed PE and a positive troponin test, even if there is no evidence of RV dysfunction on echocardiography or CT.
fThe simplified version of the PESI has not been validated in prospective home treatment trials; inclusion criteria other than the PESI were used in two single-armed (non-randomized) management studies.

38. Recommendations: acute phase treatment

40. is NOT a controversy anymore
Thrombolysis in PE
is NOT a controversy anymore