These are the slides from a presentation I recently gave at work. It demonstrates two fascinating cases [one massive & one submassive PE] & lends itself to a review of the literature assessing the roles and evidence behind thrombolysis for pulmonary embolism. Covered includes the MAPPET-3, MOPPET & PEITHO trials.

1. two in two days
Christopher Partyka
8th April 2014

2. Thrombolytics for PE
Can we alter outcomes ?!?

3. Scary statistic
Two thirds of patients who die of PE do so within
an hour of hospital presentation

4. more scary statistics...
~10% of non-traumatic sudden deaths
1 in 2 arrive in PEA/asystole
MASSIVE
~5% of PEs
58% 90 day
mortality
SUBMASSIVE
~40% of PEs
22% 90 day
mortality
MINOR
~55% of PEs
<1% 90 day
mortality

5. Massive PE
Overt right ventricular failure
Persistent systemic arterial hypotension
SBP < 90mmHg for 15mins or more
Shock
Pulselessness
~5% of cases
High mortality
Death within hours...

6. Submassive PE
A population at risk
RV dysfunction without hypotension
Dilatation or hypokinesis on ECHO
Dilatation on CT
↑ Troponin
↑ Pro-BNP
Right heart “cripples”
Chronic pulmonary HTN
Poor functionality upon DC

7. Submassive PE
RV:LV > 0.9 predicts mortality
OR 2.53 [95%CI 1.17-5.50]
Persistent RV dysfunction at discharge
4x mortality !!
8x recurrent PE
44% have chronic PHT at 1 year
Troponin elevation predicts mortality
OR 5.90 [95%CI 2.68-12.95]
Why we should care !!

8. Bust some clots ?!
Pros:
Rapid resolution of symptoms
Stabilise cardiorespiratory function
Reduce RV damage
Improve exercise tolerance
Increase probability of survival
Avoid vasopressors
Avoid intubation
We only need a 33% ↓

9. Bust some clots ?!
Cons:
Disabling or fatal haemorrhage (incl. ICH)
Blood transfusions
Unnecessary intervention (incl. surgery)
Increased hospital LOS
Risk of ICH ~ 2-3%
Risk of major bleeding ~ 22%

10. The evidence...

11. Thrombolytics for PE
What is accepted practice then ?!

12. Thrombolysis:
first line treatment for massive PE [B]
may be instituted on clinical grounds alone if cardiac
arrest is imminent [B]
a 50 mg bolus of alteplase is recommended [C]
not used as first line treatment in non-massive PE [B]

13. Thrombolysis:
first line treatment for massive PE [B]
may be instituted on clinical grounds alone if cardiac
arrest is imminent [B]
a 50 mg bolus of alteplase is recommended [C]
not used as first line treatment in non-massive PE [B]
“major haemorrhage is twice that of heparin”

15. Thrombolysis:
reasonable for massive PE w/ acceptable bleeding
risk [B]
considered for submassive PE w/ adverse prognosis
& low risk of bleeding [C]
NOT for low-risk PE [B] or undifferentiated cardiac
arrest [B]

17. Thrombolytics for PE
Blind application doesn’t work !!!

18. ~70% of OHCA result from AMI or PE
Thrombolytics during CPR may improve survival
DB RCT
original article
Thrombolysis during Resuscitation
for Out-of-Hospital Cardiac Arrest
Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D.,
Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc.,
Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D.,
Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc.,
for the TROICA Trial Investigators and the European Resuscitation
Council Study Group*
From the University of Cologne, Cologne,
and the University of Heidelberg, Heidel-
berg — both in Germany (B.W.B.); Charité,
Benjamin Franklin Medical Center, Berlin
(H.-R.A.); the Prehospital Emergency Re-
search Unit, School of Medicine, Cardiff
University,Cardiff,UnitedKingdom(D.A.C.);
Boehringer Ingelheim, Biberach, Germany
(E.B.); the Biostatistical Center, Catholic
University of Leuven, Leuven, Belgium
(A.B.);BoehringerIngelheim,Reims,France
(T.D.);Serviced’AideMédicaled’Urgence
de Paris, Hôpital Necker–Enfants Mal-
ades, Paris (P.A.C.); the Regional Medical
Cardiology Centre, Royal Victoria Hospital,
Belfast, United Kingdom (J.A.A.); Albert-
Ludwig-University, Freiburg, Germany
(C.B.); and Innsbruck Medical University,
Innsbruck, Austria (V.W.). Address reprint
requests to Dr. Böttiger at the Depart-
ment of Anesthesiology and Postopera-
tive Intensive Care Medicine, University
of Cologne, Kerpener Str. 62, Cologne
D-50937, Germany, or at bernd.boettiger@
uk-koeln.de.
*The investigators in the Thrombolysis in
Cardiac Arrest (TROICA) trial are listed
in the Appendix.
N Engl J Med 2008;359:2651-62.
Copyright © 2008 Massachusetts Medical Society.
ABSTR ACT
BACKGROUND
Approximately 70% of persons who have an out-of-hospital cardiac arrest have under-
lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis
during cardiopulmonary resuscitation may improve survival.
METHODS
In a double-blind, multicenter trial, we randomly assigned adult patients with wit-
nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio-
pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary
end point was 30-day survival; the secondary end points were hospital admission,
return of spontaneous circulation, 24-hour survival, survival to hospital discharge,
and neurologic outcome.
RESULTS
After blinded review of data from the first 443 patients, the data and safety moni-
toring board recommended discontinuation of enrollment of asystolic patients be-
cause of low survival, and the protocol was amended. Subsequently, the trial was
terminated prematurely for futility after enrolling a total of 1050 patients. Tenec-
teplase was administered to 525 patients and placebo to 525 patients; the two treat-
ment groups had similar clinical profiles. We did not detect any significant differ-
ences between tenecteplase and placebo in the primary end point of 30-day survival
(14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or
in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return
of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs.
33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neuro-
logic outcome (P=0.69). There were more intracranial hemorrhages in the tenecte-
plase group.
CONCLUSIONS
When tenecteplase was used without adjunctive antithrombotic therapy during ad-
vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement
in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)
NEJM 2008; 359:2651-62
Tenecteplase vs Placebo during cardiac-arrest

19. original article
Thrombolysis during Resuscitation
for Out-of-Hospital Cardiac Arrest
Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D.,
Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc.,
Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D.,
Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc.,
for the TROICA Trial Investigators and the European Resuscitation
Council Study Group*
From the University of Cologne, Cologne,
and the University of Heidelberg, Heidel-
berg — both in Germany (B.W.B.); Charité,
Benjamin Franklin Medical Center, Berlin
(H.-R.A.); the Prehospital Emergency Re-
search Unit, School of Medicine, Cardiff
University,Cardiff,UnitedKingdom(D.A.C.);
Boehringer Ingelheim, Biberach, Germany
(E.B.); the Biostatistical Center, Catholic
University of Leuven, Leuven, Belgium
(A.B.);BoehringerIngelheim,Reims,France
(T.D.);Serviced’AideMédicaled’Urgence
de Paris, Hôpital Necker–Enfants Mal-
ades, Paris (P.A.C.); the Regional Medical
Cardiology Centre, Royal Victoria Hospital,
Belfast, United Kingdom (J.A.A.); Albert-
Ludwig-University, Freiburg, Germany
(C.B.); and Innsbruck Medical University,
Innsbruck, Austria (V.W.). Address reprint
requests to Dr. Böttiger at the Depart-
ment of Anesthesiology and Postopera-
tive Intensive Care Medicine, University
of Cologne, Kerpener Str. 62, Cologne
D-50937, Germany, or at bernd.boettiger@
uk-koeln.de.
*The investigators in the Thrombolysis in
Cardiac Arrest (TROICA) trial are listed
in the Appendix.
N Engl J Med 2008;359:2651-62.
Copyright © 2008 Massachusetts Medical Society.
ABSTR ACT
BACKGROUND
Approximately 70% of persons who have an out-of-hospital cardiac arrest have under-
lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis
during cardiopulmonary resuscitation may improve survival.
METHODS
In a double-blind, multicenter trial, we randomly assigned adult patients with wit-
nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio-
pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary
end point was 30-day survival; the secondary end points were hospital admission,
return of spontaneous circulation, 24-hour survival, survival to hospital discharge,
and neurologic outcome.
RESULTS
After blinded review of data from the first 443 patients, the data and safety moni-
toring board recommended discontinuation of enrollment of asystolic patients be-
cause of low survival, and the protocol was amended. Subsequently, the trial was
terminated prematurely for futility after enrolling a total of 1050 patients. Tenec-
teplase was administered to 525 patients and placebo to 525 patients; the two treat-
ment groups had similar clinical profiles. We did not detect any significant differ-
ences between tenecteplase and placebo in the primary end point of 30-day survival
(14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or
in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return
of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs.
33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neuro-
logic outcome (P=0.69). There were more intracranial hemorrhages in the tenecte-
plase group.
CONCLUSIONS
When tenecteplase was used without adjunctive antithrombotic therapy during ad-
vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement
in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)
NEJM 2008; 359:2651-62The new engl and jour nal o f medicine
Table 4. Outcomes.
Outcome
Tenecteplase Group
(N=525)
Placebo Group
(N=525)
Relative Risk
(95% CI) P Value
no./total no. (%)
Primary end point
30-Day survival 77/525 (14.7) 89/525 (17.0) 0.87 (0.65–1.15) 0.36
Secondary end points
Return of spontaneous circulation 283/515 (55.0) 279/511 (54.6) 1.01 (0.90–1.13) 0.96
Hospital admission 281/525 (53.5) 289/525 (55.0) 0.97 (0.87–1.09) 0.67
24-Hr survival 158/517 (30.6) 171/514 (33.3) 0.92 (0.77–1.10) 0.39
Survival to hospital discharge 78/517 (15.1) 90/514 (17.5) 0.86 (0.65 –1.14) 0.33
Neurologic outcome* 0.69
Good cerebral performance 41/86 (47.7) 45/96 (46.9) 1.02 (0.75–1.38)
Moderate cerebral disability 13/86 (15.1) 9/96 (9.4) 1.12 (0.88–1.42)
Severe cerebral disability 10/86 (11.6) 16/96 (16.7) 1.02 (0.86–1.21)
Coma 14/86 (16.3) 18/96 (18.8) 0.99 (0.90–1.08)
Brain death 8/86 (9.3) 8/96 (8.3) 1.00
Safety end points
Symptomatic intracranial hemorrhage 4/518 (0.8) 0/514 8.93 (0.48–165.45) 0.13
Any intracranial hemorrhage 14/518 (2.7) 2/514 (0.4) 6.95 (1.59–30.41) 0.006
Major nonintracranial hemorrhage 40/517 (7.7) 33/514 (6.4) 1.21 (0.77–1.88) 0.48
Ischemic stroke 4/518 (0.8) 3/514 (0.6) 1.32 (0.30–5.88) 1.00
* Neurologic outcome is measured by cerebral performance category; categories range from 1 to 5, with 1 indicating good cerebral perfor-

20. original article
Thrombolysis during Resuscitation
for Out-of-Hospital Cardiac Arrest
Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D.,
Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc.,
Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D.,
Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc.,
for the TROICA Trial Investigators and the European Resuscitation
Council Study Group*
From the University of Cologne, Cologne,
and the University of Heidelberg, Heidel-
berg — both in Germany (B.W.B.); Charité,
Benjamin Franklin Medical Center, Berlin
(H.-R.A.); the Prehospital Emergency Re-
search Unit, School of Medicine, Cardiff
University,Cardiff,UnitedKingdom(D.A.C.);
Boehringer Ingelheim, Biberach, Germany
(E.B.); the Biostatistical Center, Catholic
University of Leuven, Leuven, Belgium
(A.B.);BoehringerIngelheim,Reims,France
(T.D.);Serviced’AideMédicaled’Urgence
de Paris, Hôpital Necker–Enfants Mal-
ades, Paris (P.A.C.); the Regional Medical
Cardiology Centre, Royal Victoria Hospital,
Belfast, United Kingdom (J.A.A.); Albert-
Ludwig-University, Freiburg, Germany
(C.B.); and Innsbruck Medical University,
Innsbruck, Austria (V.W.). Address reprint
requests to Dr. Böttiger at the Depart-
ment of Anesthesiology and Postopera-
tive Intensive Care Medicine, University
of Cologne, Kerpener Str. 62, Cologne
D-50937, Germany, or at bernd.boettiger@
uk-koeln.de.
*The investigators in the Thrombolysis in
Cardiac Arrest (TROICA) trial are listed
in the Appendix.
N Engl J Med 2008;359:2651-62.
Copyright © 2008 Massachusetts Medical Society.
ABSTR ACT
BACKGROUND
Approximately 70% of persons who have an out-of-hospital cardiac arrest have under-
lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis
during cardiopulmonary resuscitation may improve survival.
METHODS
In a double-blind, multicenter trial, we randomly assigned adult patients with wit-
nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio-
pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary
end point was 30-day survival; the secondary end points were hospital admission,
return of spontaneous circulation, 24-hour survival, survival to hospital discharge,
and neurologic outcome.
RESULTS
After blinded review of data from the first 443 patients, the data and safety moni-
toring board recommended discontinuation of enrollment of asystolic patients be-
cause of low survival, and the protocol was amended. Subsequently, the trial was
terminated prematurely for futility after enrolling a total of 1050 patients. Tenec-
teplase was administered to 525 patients and placebo to 525 patients; the two treat-
ment groups had similar clinical profiles. We did not detect any significant differ-
ences between tenecteplase and placebo in the primary end point of 30-day survival
(14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or
in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return
of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs.
33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neuro-
logic outcome (P=0.69). There were more intracranial hemorrhages in the tenecte-
plase group.
CONCLUSIONS
When tenecteplase was used without adjunctive antithrombotic therapy during ad-
vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement
in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)
NEJM 2008; 359:2651-62The new engl and jour nal o f medicine
Table 4. Outcomes.
Outcome
Tenecteplase Group
(N=525)
Placebo Group
(N=525)
Relative Risk
(95% CI) P Value
no./total no. (%)
Primary end point
30-Day survival 77/525 (14.7) 89/525 (17.0) 0.87 (0.65–1.15) 0.36
Secondary end points
Return of spontaneous circulation 283/515 (55.0) 279/511 (54.6) 1.01 (0.90–1.13) 0.96
Hospital admission 281/525 (53.5) 289/525 (55.0) 0.97 (0.87–1.09) 0.67
24-Hr survival 158/517 (30.6) 171/514 (33.3) 0.92 (0.77–1.10) 0.39
Survival to hospital discharge 78/517 (15.1) 90/514 (17.5) 0.86 (0.65 –1.14) 0.33
Neurologic outcome* 0.69
Good cerebral performance 41/86 (47.7) 45/96 (46.9) 1.02 (0.75–1.38)
Moderate cerebral disability 13/86 (15.1) 9/96 (9.4) 1.12 (0.88–1.42)
Severe cerebral disability 10/86 (11.6) 16/96 (16.7) 1.02 (0.86–1.21)
Coma 14/86 (16.3) 18/96 (18.8) 0.99 (0.90–1.08)
Brain death 8/86 (9.3) 8/96 (8.3) 1.00
Safety end points
Symptomatic intracranial hemorrhage 4/518 (0.8) 0/514 8.93 (0.48–165.45) 0.13
Any intracranial hemorrhage 14/518 (2.7) 2/514 (0.4) 6.95 (1.59–30.41) 0.006
Major nonintracranial hemorrhage 40/517 (7.7) 33/514 (6.4) 1.21 (0.77–1.88) 0.48
Ischemic stroke 4/518 (0.8) 3/514 (0.6) 1.32 (0.30–5.88) 1.00
* Neurologic outcome is measured by cerebral performance category; categories range from 1 to 5, with 1 indicating good cerebral perfor-
No survival benefit
No increase in ROSC
Increased rates of ICH in those who survived

21. MAPPET-3 Trial
ALTEPLASE IN PULMONARY EMBOLISM
HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS
WITH SUBMASSIVE PULMONARY EMBOLISM
STAVROS KONSTANTINIDES, M.D., ANNETTE GEIBEL, M.D., GERHARD HEUSEL, PH.D., FRITZ HEINRICH, M.D.,
AND WOLFGANG KASPER, M.D., FOR THE MANAGEMENT STRATEGIES AND PROGNOSIS OF PULMONARY EMBOLISM-3
TRIAL INVESTIGATORS*
ABSTRACT
Background The use of thrombolytic agents in the
treatment of hemodynamically stable patients with
acute submassive pulmonary embolism remains con-
troversial.
Methods We conducted a study of patients with
acute pulmonary embolism and pulmonary hyper-
tension or right ventricular dysfunction but without
arterial hypotension or shock. The patients were ran-
domly assigned in double-blind fashion to receive
heparin plus 100 mg of alteplase or heparin plus pla-
cebo over a period of two hours. The primary end
point was in-hospital death or clinical deterioration
requiring an escalation of treatment, which was de-
fined as catecholamine infusion, secondary throm-
bolysis, endotracheal intubation, cardiopulmonary re-
suscitation, or emergency surgical embolectomy or
thrombus fragmentation by catheter.
Results Of 256 patients enrolled, 118 were random-
ly assigned to receive heparin plus alteplase and 138
to receive heparin plus placebo. The incidence of the
primary end point was significantly higher in the hep-
HROMBOLYSIS is an established treatment
for patients with acute massive pulmonary
embolism and hemodynamic instability or
cardiogenic shock.1 In contrast, the effect of
thrombolytic agents on the outcome of hemodynam-
ically stable patients who have submassive pulmonary
embolism has been debated for decades.2,3 Several fac-
tors have contributed to the ongoing controversy: the
lack of a large, randomized study assessing clinical end
points,4 the risk of serious hemorrhage associated with
thrombolytic therapy,1,5-7 and the fact that patients’
hemodynamic status may gradually improve with hep-
arin therapy alone.8,9
The clinical data currently available underscore the
need to identify patients in whom thrombolysis may
have a favorable risk–benefit ratio. Studies based on
two large, multicenter registries reported that patients
with right ventricular dysfunction due to pulmonary
embolism had increased rates of in-hospital death, even
in the absence of arterial hypotension or shock.5,10
These findings are in accord with the results of early
T
NEJM 2002;347:1143-50

22. MAPPET-3 Trial
ALTEPLASE IN PULMONARY EMBOLISM
HEPARIN PLUS ALTEPLASE COMPARED WITH HEPARIN ALONE IN PATIENTS
WITH SUBMASSIVE PULMONARY EMBOLISM
STAVROS KONSTANTINIDES, M.D., ANNETTE GEIBEL, M.D., GERHARD HEUSEL, PH.D., FRITZ HEINRICH, M.D.,
AND WOLFGANG KASPER, M.D., FOR THE MANAGEMENT STRATEGIES AND PROGNOSIS OF PULMONARY EMBOLISM-3
TRIAL INVESTIGATORS*
ABSTRACT
Background The use of thrombolytic agents in the
treatment of hemodynamically stable patients with
acute submassive pulmonary embolism remains con-
troversial.
Methods We conducted a study of patients with
acute pulmonary embolism and pulmonary hyper-
tension or right ventricular dysfunction but without
arterial hypotension or shock. The patients were ran-
domly assigned in double-blind fashion to receive
heparin plus 100 mg of alteplase or heparin plus pla-
cebo over a period of two hours. The primary end
point was in-hospital death or clinical deterioration
requiring an escalation of treatment, which was de-
fined as catecholamine infusion, secondary throm-
bolysis, endotracheal intubation, cardiopulmonary re-
suscitation, or emergency surgical embolectomy or
thrombus fragmentation by catheter.
Results Of 256 patients enrolled, 118 were random-
ly assigned to receive heparin plus alteplase and 138
to receive heparin plus placebo. The incidence of the
primary end point was significantly higher in the hep-
HROMBOLYSIS is an established treatment
for patients with acute massive pulmonary
embolism and hemodynamic instability or
cardiogenic shock.1 In contrast, the effect of
thrombolytic agents on the outcome of hemodynam-
ically stable patients who have submassive pulmonary
embolism has been debated for decades.2,3 Several fac-
tors have contributed to the ongoing controversy: the
lack of a large, randomized study assessing clinical end
points,4 the risk of serious hemorrhage associated with
thrombolytic therapy,1,5-7 and the fact that patients’
hemodynamic status may gradually improve with hep-
arin therapy alone.8,9
The clinical data currently available underscore the
need to identify patients in whom thrombolysis may
have a favorable risk–benefit ratio. Studies based on
two large, multicenter registries reported that patients
with right ventricular dysfunction due to pulmonary
embolism had increased rates of in-hospital death, even
in the absence of arterial hypotension or shock.5,10
These findings are in accord with the results of early
T
NEJM 2002;347:1143-50

23. MAPPET-3 Trial
DB RCT
Acute PE with RV strain
- ECG
- ECHO
- CT
Heparin plus 100mg alteplase
vs
Heparin plus placebo

24. MAPPET-3 Trial
DB RCT
Acute PE with RV strain
- ECG
- ECHO
- CT
No difference shown for in-hospital mortality
(3.4% vs 2.2%; p=0.71)
More cases of clinical deterioration requiring
therapy escalation in heparin-alone group
(24.6% vs 10.2%; p=0.004)
Only 31% had ECHO confirmation
of RV strain !!

25. MAPPET-3 TrialThe New England Journal of Medicine
*The numbers shown are based on calculations for the intention-to-treat population.
†P values were calculated with the use of Fisher’s exact test (two-sided).
TABLE 2. IN-HOSPITAL CLINICAL EVENTS.*
EVENT
HEPARIN PLUS
ALTEPLASE
(N=118)
HEPARIN PLUS
PLACEBO
(N=138) P VALUE†
no. (%)
Primary end point 13 (11.0) 34 (24.6) 0.006
Death from all causes 4 (3.4) 3 (2.2) 0.71
Escalation of treatment 12 (10.2) 34 (24.6) 0.004
Catecholamine infusion
(for persistent hypotension or shock)
3 (2.5) 8 (5.8) 0.33
Secondary thrombolysis 9 (7.6) 32 (23.2) 0.001
Endotracheal intubation 3 (2.5) 3 (2.2) 0.85
Cardiopulmonary resuscitation 0 1 (0.7) 1.0
Embolectomy or thrombus fragmentation 0 1 (0.7) 1.0
Secondary end points
Recurrent pulmonary embolism‡ 4 (3.4) 4 (2.9) 0.89
Major bleeding§ 1 (0.8) 5 (3.6) 0.29
Fatal bleeding 0 1 (0.7) 1.0
Hemorrhagic stroke¶ 0 0 —
Ischemic stroke¶ 0 1 (0.7) 1.0

26. The “MOPPET” trial
Moderate Pulmonary Embolism Treated With Thrombolysis
(from the “MOPETT” Trial)
Mohsen Sharifi, MDa,b,
*, Curt Bay, PhDb
, Laura Skrocki, DOa
, Farnoosh Rahimi, MDa
,
and Mahshid Mehdipour, DMDa,b
, “MOPETT” Investigators
The role of low-dose thrombolysis in the reduction of pulmonary artery pressure in
moderate pulmonary embolism (PE) has not been investigated. Because the lungs are very
sensitive to thrombolysis, we postulated that effective and safe thrombolysis might be
achieved by a lower dose of tissue plasminogen activator. The purpose of the present study
was to evaluate the role of this “safe dose” thrombolysis in the reduction of pulmonary
artery pressure in moderate PE. During a 22-month period, 121 patients with moderate PE
were randomized to receive a “safe dose” of tissue plasminogen activator plus anti-
coagulation (thrombolysis group [TG], n [ 61 patients) or anticoagulation alone (control
group [CG], n [ 60). The primary end points consisted of pulmonary hypertension and the
composite end point of pulmonary hypertension and recurrent PE at 28 months. Pulmonary
hypertension and the composite end point developed in 9 of 58 patients (16%) in the TG
and 32 of 56 patients (57%) in the CG (p <0.001) and 9 of 58 patients (16%) in the TG and
35 of 56 patients (63%) in the CG (p <0.001), respectively. The secondary end points were
total mortality, the duration of hospital stay, bleeding at the index hospitalization, recurrent
PE, and the combination of mortality and recurrent PE. The duration of hospitalization was
2.2 – 0.5 days in the TG and 4.9 – 0.8 days in the CG (p <0.001). The combination of death
plus recurrent PE was 1 (1.6%) in TG and 6 (10%) in the CG (p [ 0.0489). No bleeding
occurred in any group, and despite a positive trend in favor of a “safe dose” thrombolysis,
no significant difference was noted in the rate of individual outcomes of death and recurrent
PE when assessed independently. In conclusion, the results from the present prospective
randomized trial suggests that “safe dose” thrombolysis is safe and effective in the treat-
ment of moderate PE, with a significant immediate reduction in the pulmonary artery
pressure that was maintained at 28 months. Ó 2013 Elsevier Inc. All rights reserved. (Am
AM J Cardiol 2013;111:273e277
Half dose t-PA for submassive
(moderate) PE

27. The “MOPPET” trial
Single-centre, randomised
“half dose” t-PA vs control [no placebo]
Unwell patients w/ moderate PE
Anatomical defn of ‘submassive’
ECHO not required
prior to enrolment

28. The “MOPPET” trial
Theory:
PE is exquisitely sensitive to 'lytics
the lungs see 100% of the circulation
Brain ~ 15%
Myocardium ~5%
lower dose → lower complications

29. The “MOPPET” trial
Primary endpoints:
Pulmonary HTN
Recurrent PE

30. The “MOPPET” trial
Primary endpoints:
Pulmonary HTN
Recurrent PE
Pulmonary HTN at 28 months:
16% vs 57%, p<0.001

31. The “MOPPET” trial
Secondary endpoints:
Total mortality
Hospital LOS
Bleeding
Recurrent PE

32. The “MOPPET” trial
Secondary endpoints:
Total mortality
Hospital LOS
Bleeding
Recurrent PE
Benefits:
↓ recurrent PE - 0% vs 5%, p=0.08
↓ hospital LOS - 2.2 vs 4.9 days, p<0.001
Indifferences:
Total mortality
Bleeding - none in either group

33. PEITHO trial
American Heart Journal, 163(1), 33–38.e1.

34. PEITHO trial
Prospective, international, MC, DB, RCT
Tenecteplase vs placebo
+ standard anticoagulation
1006 normotensive patients w/ confirmed PE +
abnormal RV on ECHO or CT and
elevated troponin

35. PEITHO trial
Table I. Inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
(1) Age 18 y (1) Hemodynamic collapse at presentation⁎⁎
(2) Acute PE (first symptoms 15 d or less before randomization) confirmed by
lung scan, or a positive computed tomographic pulmonary angiogram,
or a positive selective pulmonary angiogram
(2) Known significant bleeding risk
(3) RV dysfunction confirmed by echocardiography or spiral computed
tomography of the chest
(3) Administration of a thrombolytic agent in the previous 4 d
Echocardiography (≥1 criterion)
(4) Vena cava filter insertion or pulmonary thrombectomy in the previous 4 d
• RV end-diastolic diameter N30 mm (parasternal long axis or short axis)
(5) Uncontrolled hypertension (systolic BP N180 mm Hg and/or diastolic BP
N110 mm Hg at randomization)
• Right/left ventricular end-diastolic diameter N0.9
(apical or subcostal 4-chamber view)
(6) Treatment with an investigational drug under another study protocol in
the previous 7 d or longer, according to local requirements
• Hypokinesis of RV-free wall (any view)
(7) Previous enrollment in this study
• Tricuspid regurgitant jet velocity N2.6 m/s
(8) Known hypersensitivity to tenecteplase, alteplase, UFH, or any of the
excipients
Computed tomography
(9) Pregnancy, lactation, or parturition within the previous 30 d; women of
childbearing age must have a negative pregnancy test or use a medically
accepted method of birth control• Right/left short-axis diameter ratio N0.9 (transverse plane)
(10) Known coagulation disorder (including use of vitamin K antagonists
and platelet count b100,000/mm3
)
(4) Myocardial injury confirmed by a positive troponin I or T test result⁎ (11) Any other condition that the investigator feels would place the patient at
increased risk if the investigational therapy were administered
BP denotes blood pressure.
⁎ Cutoff levels for defining elevating troponin I or T levels are defined by the Department of Clinical Chemistry at each participating site.
⁎⁎ At least 1 of the following: (i) the need for cardiopulmonary resuscitation; (ii) systolic blood pressure b90 mm Hg for at least 15 minutes, or a drop of systolic blood pressure by at
least 40 mm Hg for at least 15 minutes, with signs of end-organ hypoperfusion (cold extremities, urinary output b30 mL/h, or mental confusion); and (iii) the need for catecholamines
(except for dopamine at a rate of ≤5 μg kg−1
min−1
) to maintain adequate organ perfusion and a systolic blood pressure of N90 mm Hg.
The Steering Committee 35
American Heart Journal
Volume 163, Number 1

36. PEITHO trial
hypotheses are as follows: H0: 7-day-death-hemcoltenect =
7-day-death-hemcolplacebo vs H1: 7day-death-hemcoltenect ≠
7day-death-hemcol (where hemcol stands for he-
Figure 1
Confirmed
acute
E
comes
acute
symptomatic
PE
Absence of
TNK §
DOUBLE
omes,SAE
daryOutc
hemodynamic
collapse* UFH infusion ‡
ow-up
<2 h
UFH, LMWH or
Fondaparinux
R
DOUBLE
BLIND
VKA
nrayOuto
me,Secon
Confirmed RV
dysfunction +
myocardial
injury**
-termFollo
Placebo §
Seco
ryOutcom
UFH infusion ‡
UFH, LMWH or
Fondaparinux
Long-
Prima
VKAUFH bolus
i.v. †
Day 2 Day 7 Day 30 Day 180
Flow diagram of the Pulmonary Embolism International Thrombolysis trial. RV indicates right ventricular (dysfunction); TNK, tenecteplase;
VKA, vitamin K antagonists. *As defined in Table I; **criteria defined in Table I; †
at a dosage of 80 IU/kg of body weight; ‡
initial infusion rate,
18 IU/kg/h; §
the dosing regimen for tenecteplase (or placebo) is shown in Table II.
Table II. Tenecteplase dosing regimen
Weight (kg) Dose (mg) Dose (Units) Volume (mL)
36 The Steering Committee
American Heart Journal
January 2012

37. PEITHO trial
Primary outcome
Death or
Haemodynamic collapse =
CPR
SBP < 90 for ≥15mins
End-organ hypo perfusion
Vasopressor requirement
within 7 days...

38. PEITHO trial
Primary outcome
Death or
Haemodynamic collapse =
CPR
SBP < 90 for ≥15mins
End-organ hypo perfusion
Vasopressor requirement
Primary Outcome
t-PA 2.6% vs Placebo 5.6%, p=0.015
RRR 54%
HD collapse
t-PA 1.6% vs Placebo 5.0%, p=0.002
esp. hypotension & vasopressor req.
No difference in 7-day mortality.

40. PEITHO trial
Safety outcomes
Ischaemic or haemorrhagic stroke in 7 days
Other major bleeding = Fatal bleeding
Blood transfusion req'd
Inotropic support req'd
Emergent surgical
intervention

41. PEITHO trial
Safety outcomes
Ischaemic or haemorrhagic stroke in 7 days
Other major bleeding = Fatal bleeding
Blood transfusion req'd
Inotropic support req'd
Emergent surgical
intervention
Increased risk of major & minor bleeding.
MAJOR: 6.3% vs 1.5%, p<0.001
MINOR: 32.6% vs 8.6%, p<0.001
Stroke: 2.4% vs 0.2%, p=0.003

42. PEITHO
No difference in 30-day
mortality.

43. Finally; the MOPPET crew
return in 2014...

44. Prospective, observational study.
98 consecutive patients with moderate to severe PE
“safe-dose” t-PA + heparin followed by rivaroxaban
ECHO followed for pulmonary HTN
Address for correspondence:
Mohsen Sharifi, MD,
Arizona Cardiovascular Consultants
and Vein Clinic, 3850 E. Baseline
Road, Building 1, Suite 102, Mesa, AZ
85206.
seyedmohsensharifi@yahoo.com
Clinical Investigations
Safe-Dose Thrombolysis Plus Rivaroxaban for
Moderate and Severe Pulmonary Embolism:
Drip, Drug, and Discharge
Mohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DO
Arizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. Still
University (Sharifi, Bay, Schwartz), Mesa, Arizona
Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic
pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the
treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and
rivaroxaban in PE.
Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become an
appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby
drastically reducing hospitalization time.
Methods: Over a 12-month period, 98 consecutive patients with symptomatic PE were treated by a combination
of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours.
Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination
of heparin infusion.
Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to
warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2
months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg
within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was
1.9 ± 0.2 days.
Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment of
moderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge.
Introduction
Over the last few years, new oral anticoagulants have
been introduced that can replace vitamin K antagonists
in patients with pulmonary embolism (PE).1,2 The trials
not been previously reported. This study describes our
experience with the combination of SDT and rivaroxaban
for the treatment of moderate and severe PE.
Clin. Cardiol. 37(2) 78–82 (2014)

45. Address for correspondence:
Mohsen Sharifi, MD,
Arizona Cardiovascular Consultants
and Vein Clinic, 3850 E. Baseline
Road, Building 1, Suite 102, Mesa, AZ
85206.
seyedmohsensharifi@yahoo.com
Clinical Investigations
Safe-Dose Thrombolysis Plus Rivaroxaban for
Moderate and Severe Pulmonary Embolism:
Drip, Drug, and Discharge
Mohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DO
Arizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. Still
University (Sharifi, Bay, Schwartz), Mesa, Arizona
Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic
pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the
treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and
rivaroxaban in PE.
Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become an
appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby
drastically reducing hospitalization time.
Methods: Over a 12-month period, 98 consecutive patients with symptomatic PE were treated by a combination
of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours.
Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination
of heparin infusion.
Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to
warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2
months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg
within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was
1.9 ± 0.2 days.
Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment of
moderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge.
Introduction
Over the last few years, new oral anticoagulants have
been introduced that can replace vitamin K antagonists
in patients with pulmonary embolism (PE).1,2 The trials
not been previously reported. This study describes our
experience with the combination of SDT and rivaroxaban
for the treatment of moderate and severe PE.
Clin. Cardiol. 37(2) 78–82 (2014)
Patients, N = 98
47 (48)
56 ± 10
81 ± 11
28 ± 3
54 (55)
34 (35)
32 (33)
12 (12)
5 (5)
5 (5)

46. Address for correspondence:
Mohsen Sharifi, MD,
Arizona Cardiovascular Consultants
and Vein Clinic, 3850 E. Baseline
Road, Building 1, Suite 102, Mesa, AZ
85206.
seyedmohsensharifi@yahoo.com
Clinical Investigations
Safe-Dose Thrombolysis Plus Rivaroxaban for
Moderate and Severe Pulmonary Embolism:
Drip, Drug, and Discharge
Mohsen Sharifi, MD; Curt Bay, PhD; Frederic Schwartz, DO; Laura Skrocki, DO
Arizona Cardiovascular Consultants and Vein Clinic (Sharifi, Skrocki), Mesa, Arizona; A. T. Still
University (Sharifi, Bay, Schwartz), Mesa, Arizona
Background: Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic
pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the
treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and
rivaroxaban in PE.
Hypothesis: ‘‘Safe dose’’ thrombolysis (SDT) plus new oral anticoagulants are expected to become an
appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby
drastically reducing hospitalization time.
Methods: Over a 12-month period, 98 consecutive patients with symptomatic PE were treated by a combination
of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours.
Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination
of heparin infusion.
Results: There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to
warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow-up of 12 ± 2
months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg
within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was
1.9 ± 0.2 days.
Conclusions: ‘‘Safe dose’’ thrombolysis plus rivaroxaban is highly safe and effective in the treatment of
moderate and severe PE, leading to favorable early and intermediate-term outcomes and early discharge.
Introduction
Over the last few years, new oral anticoagulants have
been introduced that can replace vitamin K antagonists
in patients with pulmonary embolism (PE).1,2 The trials
not been previously reported. This study describes our
experience with the combination of SDT and rivaroxaban
for the treatment of moderate and severe PE.
Clin. Cardiol. 37(2) 78–82 (2014)
No significant major or minor bleeding
1x psoas haematoma
1x gross haematuria
3 recurrent VTE [on warfarin]
2 had cancer
Hospital LOS 1.9 ± 0.2 days

47. now we are enlightened...
... back to our tales !!